CORD-19-Sentences  

CORD-19:066ec24d68f5a0f78a3e6684da8a33fdb7368f58 JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-66 Sentence denotes Inhibitory and Coactivating Receptors Recognising the Same Ligand:
TextSentencer_T1 0-66 Sentence denotes Inhibitory and Coactivating Receptors Recognising the Same Ligand:
TextSentencer_T2 67-120 Sentence denotes Immune Homeostasis Exploited by Pathogens and Tumours
TextSentencer_T2 67-120 Sentence denotes Immune Homeostasis Exploited by Pathogens and Tumours
TextSentencer_T3 122-130 Sentence denotes Abstract
TextSentencer_T3 122-130 Sentence denotes Abstract
TextSentencer_T4 131-294 Sentence denotes Coactivating and inhibitory receptors that share at least one ligand interact with a wide variety of ligands, indicating their importance in a range of situations.
TextSentencer_T4 131-294 Sentence denotes Coactivating and inhibitory receptors that share at least one ligand interact with a wide variety of ligands, indicating their importance in a range of situations.
TextSentencer_T5 295-499 Sentence denotes Here, we discuss principles of mainly human paired receptor function and ligand recognition, and possible therapeutic implications of targeting these receptors in cancer, autoimmune diseases, and allergy.
TextSentencer_T5 295-499 Sentence denotes Here, we discuss principles of mainly human paired receptor function and ligand recognition, and possible therapeutic implications of targeting these receptors in cancer, autoimmune diseases, and allergy.
TextSentencer_T6 500-809 Sentence denotes We summarise and emphasise the idea that these receptors, which have evolved in part in response to pathogen pressure, fine-tune the immune response, preserve homeostasis, and that pathogens and tumours use the dominance of the inhibitory receptors over the coactivating receptors to avoid immune elimination.
TextSentencer_T6 500-809 Sentence denotes We summarise and emphasise the idea that these receptors, which have evolved in part in response to pathogen pressure, fine-tune the immune response, preserve homeostasis, and that pathogens and tumours use the dominance of the inhibitory receptors over the coactivating receptors to avoid immune elimination.
TextSentencer_T7 810-923 Sentence denotes Finally, we discuss the options of using paired receptors and their ligand for immune cell education and therapy.
TextSentencer_T7 810-923 Sentence denotes Finally, we discuss the options of using paired receptors and their ligand for immune cell education and therapy.
TextSentencer_T8 925-1162 Sentence denotes Current models of immunological activation have expanded our knowledge from single ligandreceptor interactions to integrated models in which several receptors have a combinatorial role in the activation of a specific type of immune cell.
TextSentencer_T8 925-1162 Sentence denotes Current models of immunological activation have expanded our knowledge from single ligandreceptor interactions to integrated models in which several receptors have a combinatorial role in the activation of a specific type of immune cell.
TextSentencer_T9 1163-1422 Sentence denotes The model of T cell activation is a clear example of this; whereas the canonical T cell receptor (TCR) is thought to provide the primary activating signal, co-stimulatory receptors and soluble factors have become integral parts of a more complex picture [1] .
TextSentencer_T9 1163-1422 Sentence denotes The model of T cell activation is a clear example of this; whereas the canonical T cell receptor (TCR) is thought to provide the primary activating signal, co-stimulatory receptors and soluble factors have become integral parts of a more complex picture [1] .
TextSentencer_T10 1423-1635 Sentence denotes Similarly, mast cells are primarily activated by the IgE receptors (such as FceRI), but soluble factors, inhibitory, activating, and coactivating receptors can together modulate the activities of mast cells [2] .
TextSentencer_T10 1423-1635 Sentence denotes Similarly, mast cells are primarily activated by the IgE receptors (such as FceRI), but soluble factors, inhibitory, activating, and coactivating receptors can together modulate the activities of mast cells [2] .
TextSentencer_T11 1636-1728 Sentence denotes The complexity of immunological signalling is best exemplified in natural killer (NK) cells.
TextSentencer_T11 1636-1728 Sentence denotes The complexity of immunological signalling is best exemplified in natural killer (NK) cells.
TextSentencer_T12 1729-2010 Sentence denotes In these cells, no single receptor is ultimately responsible for cellular activation; rather, a balance of signals from a wide variety of activating receptors, coactivating receptors, and inhibitory receptors (again, together with soluble factors) determines NK cell activity [3] .
TextSentencer_T12 1729-2010 Sentence denotes In these cells, no single receptor is ultimately responsible for cellular activation; rather, a balance of signals from a wide variety of activating receptors, coactivating receptors, and inhibitory receptors (again, together with soluble factors) determines NK cell activity [3] .
TextSentencer_T13 2011-2196 Sentence denotes A more comprehensive understanding of these integrative signalling processes has recently become of great clinical significance owing to the development of immune checkpoint inhibitors.
TextSentencer_T13 2011-2196 Sentence denotes A more comprehensive understanding of these integrative signalling processes has recently become of great clinical significance owing to the development of immune checkpoint inhibitors.
TextSentencer_T14 2197-2556 Sentence denotes Inhibitory and coactivating receptors that recognise the same cellular ligandswhich we refer to here as paired receptors (for a broader definition of the previous one, see Trends)are the focus of this review ( Figure 1A ); see also a brief description of these receptors in [4] and selected examples in [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] .
TextSentencer_T14 2197-2556 Sentence denotes Inhibitory and coactivating receptors that recognise the same cellular ligandswhich we refer to here as paired receptors (for a broader definition of the previous one, see Trends)are the focus of this review ( Figure 1A ); see also a brief description of these receptors in [4] and selected examples in [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] .
TextSentencer_T15 2557-2637 Sentence denotes We first discuss how paired receptors are defined and how they may have evolved.
TextSentencer_T15 2557-2637 Sentence denotes We first discuss how paired receptors are defined and how they may have evolved.
TextSentencer_T16 2638-2893 Sentence denotes We describe their complex expression patterns and determine what controls their Trends Paired receptors were initially described as activating and inhibitory receptors homologous in their extracellular domains and located in close proximity on the genome.
TextSentencer_T16 2638-2893 Sentence denotes We describe their complex expression patterns and determine what controls their Trends Paired receptors were initially described as activating and inhibitory receptors homologous in their extracellular domains and located in close proximity on the genome.
TextSentencer_T17 2894-3144 Sentence denotes Here we give a broader definition, as a pair of receptors that includes an inhibitory and a coactivating receptor; where each member has at least one common cellular ligand, and upon binding, exerts contrasting effects (inhibition or co-stimulation).
TextSentencer_T17 2894-3144 Sentence denotes Here we give a broader definition, as a pair of receptors that includes an inhibitory and a coactivating receptor; where each member has at least one common cellular ligand, and upon binding, exerts contrasting effects (inhibition or co-stimulation).
TextSentencer_T18 3145-3267 Sentence denotes In these pairs, the inhibitory receptor binds the shared ligand with greater affinity than does the coactivating receptor.
TextSentencer_T18 3145-3267 Sentence denotes In these pairs, the inhibitory receptor binds the shared ligand with greater affinity than does the coactivating receptor.
TextSentencer_T19 3268-3358 Sentence denotes This high-affinity binding of the inhibitory receptor results also in competitive binding.
TextSentencer_T19 3268-3358 Sentence denotes This high-affinity binding of the inhibitory receptor results also in competitive binding.
TextSentencer_T20 3359-3505 Sentence denotes Some of the inhibitory receptors can also exert their function by physically interacting with the activating receptor and preventing its activity.
TextSentencer_T20 3359-3505 Sentence denotes Some of the inhibitory receptors can also exert their function by physically interacting with the activating receptor and preventing its activity.
TextSentencer_T21 3506-3613 Sentence denotes Inhibitory receptors and ligands for paired receptors are used by pathogens and tumours for immune evasion.
TextSentencer_T21 3506-3613 Sentence denotes Inhibitory receptors and ligands for paired receptors are used by pathogens and tumours for immune evasion.
TextSentencer_T22 3614-3625 Sentence denotes activities.
TextSentencer_T22 3614-3625 Sentence denotes activities.
TextSentencer_T23 3626-3791 Sentence denotes We hypothesise that the paired receptors that have probably evolved mainly in response to pathogens are now also used to maintain immune cells in a responsive state.
TextSentencer_T23 3626-3791 Sentence denotes We hypothesise that the paired receptors that have probably evolved mainly in response to pathogens are now also used to maintain immune cells in a responsive state.
TextSentencer_T24 3792-3989 Sentence denotes We further suggest that they also limit overzealous inflammation by dampening the activation signals provided by the coactivating receptors that could (at least in some cases) lead to autoimmunity.
TextSentencer_T24 3792-3989 Sentence denotes We further suggest that they also limit overzealous inflammation by dampening the activation signals provided by the coactivating receptors that could (at least in some cases) lead to autoimmunity.
TextSentencer_T25 3990-4110 Sentence denotes Furthermore, we discuss how pathogens manipulate paired receptors, to infect cells and subsequently evade immune attack.
TextSentencer_T25 3990-4110 Sentence denotes Furthermore, we discuss how pathogens manipulate paired receptors, to infect cells and subsequently evade immune attack.
TextSentencer_T26 4111-4375 Sentence denotes Finally, we examine the potential use of the paired receptors as therapeutic targets in various clinical situations and propose that the paired receptors might be involved in immune cell education; the process by which immune cells acquire functional capabilities.
TextSentencer_T26 4111-4375 Sentence denotes Finally, we examine the potential use of the paired receptors as therapeutic targets in various clinical situations and propose that the paired receptors might be involved in immune cell education; the process by which immune cells acquire functional capabilities.
TextSentencer_T27 4376-4624 Sentence denotes Historically, studies of mouse receptors, such as the Ly49 receptor family on NK cells [also known as the killer cell lectin-like receptor subfamily A (KLRA) family], significantly contributed to the concept of paired receptors (reviewed in [17] ).
TextSentencer_T27 4376-4624 Sentence denotes Historically, studies of mouse receptors, such as the Ly49 receptor family on NK cells [also known as the killer cell lectin-like receptor subfamily A (KLRA) family], significantly contributed to the concept of paired receptors (reviewed in [17] ).
TextSentencer_T28 4625-4775 Sentence denotes Due to text limitations we are not able to elaborate on all possible aspects of all of the paired receptors and we instead highlight several examples.
TextSentencer_T28 4625-4775 Sentence denotes Due to text limitations we are not able to elaborate on all possible aspects of all of the paired receptors and we instead highlight several examples.
TextSentencer_T29 4776-4986 Sentence denotes Furthermore, although there are many known paired receptors, both in humans and in mice, we focus mainly on a few well-characterised human pairs that enable us to best present the general principles we outline.
TextSentencer_T29 4776-4986 Sentence denotes Furthermore, although there are many known paired receptors, both in humans and in mice, we focus mainly on a few well-characterised human pairs that enable us to best present the general principles we outline.
TextSentencer_T30 4987-5348 Sentence denotes In that regard, we do not discuss here paired receptors in which the inhibitory and the activating proteins that recognise the same ligand are not well defined [such as the leukocyte immunoglobulin-like receptor (LILR) family], or receptors in which one of the pair seemed not to function in humans (such as paired immunoglobulin-like type 2 receptor a; PILRA).
TextSentencer_T30 4987-5348 Sentence denotes In that regard, we do not discuss here paired receptors in which the inhibitory and the activating proteins that recognise the same ligand are not well defined [such as the leukocyte immunoglobulin-like receptor (LILR) family], or receptors in which one of the pair seemed not to function in humans (such as paired immunoglobulin-like type 2 receptor a; PILRA).
TextSentencer_T31 5349-5542 Sentence denotes Paired receptors were initially described as activating and inhibitory receptors that are highly homologous in their extracellular domains and that are located in close proximity on the genome.
TextSentencer_T31 5349-5542 Sentence denotes Paired receptors were initially described as activating and inhibitory receptors that are highly homologous in their extracellular domains and that are located in close proximity on the genome.
TextSentencer_T32 5543-5660 Sentence denotes These receptors, which recognise the same cellular ligands, seemed to evolve together through gene duplication [18] .
TextSentencer_T32 5543-5660 Sentence denotes These receptors, which recognise the same cellular ligands, seemed to evolve together through gene duplication [18] .
TextSentencer_T33 5661-5832 Sentence denotes Paired receptors belong to many different families of molecules, and they include members of the immunoglobulin superfamily, lectin family, and lectin-like protein family.
TextSentencer_T33 5661-5832 Sentence denotes Paired receptors belong to many different families of molecules, and they include members of the immunoglobulin superfamily, lectin family, and lectin-like protein family.
TextSentencer_T34 5833-6778 Sentence denotes Today, receptors that are not located next to each other on the genome, such as the inhibitory receptor TIGIT (T cell immunoreceptor with immunglobulin and ITIM domains), the coactivating receptor DNAM1 (DNAX accessory molecule 1; also known as The inhibitory receptor (marked in red), has a higher affinity for the shared ligand than the activating receptor in all receptor pairs (for example, TIGIT versus DNAM1 [8, 38] ). (B2) As a result of its higher affinity for ligand, the inhibitory receptor competes with its activating partner for ligand binding such that the inhibitory receptor physically interrupts the binding of the activating receptor to the ligand [8, 38] . (B3) There is also evidence that inhibitory receptors can interfere with the homodimerization of their corresponding activating receptor, thereby preventing signalling through the activating receptor (e.g., TIGIT can interfere with the homodimerisation of DNAM1 [20] ).
TextSentencer_T34 5833-6778 Sentence denotes Today, receptors that are not located next to each other on the genome, such as the inhibitory receptor TIGIT (T cell immunoreceptor with immunglobulin and ITIM domains), the coactivating receptor DNAM1 (DNAX accessory molecule 1; also known as The inhibitory receptor (marked in red), has a higher affinity for the shared ligand than the activating receptor in all receptor pairs (for example, TIGIT versus DNAM1 [8, 38] ). (B2) As a result of its higher affinity for ligand, the inhibitory receptor competes with its activating partner for ligand binding such that the inhibitory receptor physically interrupts the binding of the activating receptor to the ligand [8, 38] . (B3) There is also evidence that inhibitory receptors can interfere with the homodimerization of their corresponding activating receptor, thereby preventing signalling through the activating receptor (e.g., TIGIT can interfere with the homodimerisation of DNAM1 [20] ).
TextSentencer_T35 6779-6893 Sentence denotes Abbreviations: DNAM1, DNAX accessory molecule 1; TIGIT, T cell immunoreceptor with immunglobulin and ITIM domains.
TextSentencer_T35 6779-6893 Sentence denotes Abbreviations: DNAM1, DNAX accessory molecule 1; TIGIT, T cell immunoreceptor with immunglobulin and ITIM domains.
TextSentencer_T36 6894-7150 Sentence denotes CD226), and the inhibitory receptor CD112R (also known as PVRIG), can also be considered to be paired receptors as they recognise the same cellular ligands (mainly the poliovirus receptor PVR), but have opposing effects (inhibition and coactivation) [19] .
TextSentencer_T36 6894-7150 Sentence denotes CD226), and the inhibitory receptor CD112R (also known as PVRIG), can also be considered to be paired receptors as they recognise the same cellular ligands (mainly the poliovirus receptor PVR), but have opposing effects (inhibition and coactivation) [19] .
TextSentencer_T37 7151-7506 Sentence denotes For the purpose of this article, we therefore define paired receptors as a pair of receptors that includes an inhibitory and a coactivating receptor; each member of the pair has at least one common cellular ligand (Table 1) , and upon binding of this ligand, each member of the pair exerts contrasting effects (inhibition or co-stimulation) ( Figure 1A ).
TextSentencer_T37 7151-7506 Sentence denotes For the purpose of this article, we therefore define paired receptors as a pair of receptors that includes an inhibitory and a coactivating receptor; each member of the pair has at least one common cellular ligand (Table 1) , and upon binding of this ligand, each member of the pair exerts contrasting effects (inhibition or co-stimulation) ( Figure 1A ).
TextSentencer_T38 7507-7762 Sentence denotes Note that paired receptors in the context of this article do not need to be functionally linked and can signal independently of each otherin other words, the inhibitory receptor does not need to directly inhibit signalling through the activating receptor.
TextSentencer_T38 7507-7762 Sentence denotes Note that paired receptors in the context of this article do not need to be functionally linked and can signal independently of each otherin other words, the inhibitory receptor does not need to directly inhibit signalling through the activating receptor.
TextSentencer_T39 7763-7999 Sentence denotes NK cells, which express numerous activating and inhibitory receptors, with no single dominant activating receptor, thus function mainly as balanced effectors, indeed express the widest variety of these paired receptors (Table 1 ) [19] .
TextSentencer_T39 7763-7999 Sentence denotes NK cells, which express numerous activating and inhibitory receptors, with no single dominant activating receptor, thus function mainly as balanced effectors, indeed express the widest variety of these paired receptors (Table 1 ) [19] .
TextSentencer_T40 8000-8289 Sentence denotes Interestingly, the paired receptors, identified so far, do not include independently functioning, bona fide activating receptors that function independently [such as CD16 on naïve NK cells, NKG2D and the natural cytotoxicity receptors (NCRs) on activated NK cells, or FceRI on mast cells].
TextSentencer_T40 8000-8289 Sentence denotes Interestingly, the paired receptors, identified so far, do not include independently functioning, bona fide activating receptors that function independently [such as CD16 on naïve NK cells, NKG2D and the natural cytotoxicity receptors (NCRs) on activated NK cells, or FceRI on mast cells].
TextSentencer_T41 8290-8411 Sentence denotes Instead, it is coactivating receptors (that do not function independently) that are paired with the inhibitory receptors.
TextSentencer_T41 8290-8411 Sentence denotes Instead, it is coactivating receptors (that do not function independently) that are paired with the inhibitory receptors.
TextSentencer_T42 8412-8603 Sentence denotes For the paired receptors, the inhibitory receptor seems to bind the shared ligand with greater affinity than does the coactivating receptor, as determined by in vitro assays (Table 1 ) [19] .
TextSentencer_T42 8412-8603 Sentence denotes For the paired receptors, the inhibitory receptor seems to bind the shared ligand with greater affinity than does the coactivating receptor, as determined by in vitro assays (Table 1 ) [19] .
TextSentencer_T43 8604-8929 Sentence denotes Although in vitro affinities may not accurately reflect the cell membrane environment in vivo, these observations suggest that under healthy, steady-state conditions, when the inhibitory receptor and coactivating receptor are expressed on the same cell bind their shared ligand, the dominant signal is most likely inhibition.
TextSentencer_T43 8604-8929 Sentence denotes Although in vitro affinities may not accurately reflect the cell membrane environment in vivo, these observations suggest that under healthy, steady-state conditions, when the inhibitory receptor and coactivating receptor are expressed on the same cell bind their shared ligand, the dominant signal is most likely inhibition.
TextSentencer_T44 8930-9145 Sentence denotes This high-affinity binding of the inhibitory receptor also results in competitive binding, whereby the inhibitory receptors physically interrupt the binding of the coactivating receptors to the ligand ( Figure 1B ).
TextSentencer_T44 8930-9145 Sentence denotes This high-affinity binding of the inhibitory receptor also results in competitive binding, whereby the inhibitory receptors physically interrupt the binding of the coactivating receptors to the ligand ( Figure 1B ).
TextSentencer_T45 9146-9253 Sentence denotes In addition, some of the inhibitory receptors can also exert their function in a receptor-extrinsic manner.
TextSentencer_T45 9146-9253 Sentence denotes In addition, some of the inhibitory receptors can also exert their function in a receptor-extrinsic manner.
TextSentencer_T46 9254-9460 Sentence denotes For example, the inhibitory receptor TIGIT has been shown to disrupt the homodimerisation of its binding partner DNAM1, thus interfering with the coactivating receptor function of DNAM1 ( Figure 1B ) [20] .
TextSentencer_T46 9254-9460 Sentence denotes For example, the inhibitory receptor TIGIT has been shown to disrupt the homodimerisation of its binding partner DNAM1, thus interfering with the coactivating receptor function of DNAM1 ( Figure 1B ) [20] .
TextSentencer_T47 9461-9678 Sentence denotes Activating and coactivating receptors signal mainly through immunoreceptor tyrosine-based activation motifs (ITAMs), whereas inhibitory receptors signal through immunoreceptor tyrosine-based inhibitory motifs (ITIMs).
TextSentencer_T47 9461-9678 Sentence denotes Activating and coactivating receptors signal mainly through immunoreceptor tyrosine-based activation motifs (ITAMs), whereas inhibitory receptors signal through immunoreceptor tyrosine-based inhibitory motifs (ITIMs).
TextSentencer_T48 9679-9856 Sentence denotes Several of the coactivating paired receptors have an ITIM sequence in the 3 0 untranslated region, which suggests that they may have evolved from the inhibitory receptors [18] .
TextSentencer_T48 9679-9856 Sentence denotes Several of the coactivating paired receptors have an ITIM sequence in the 3 0 untranslated region, which suggests that they may have evolved from the inhibitory receptors [18] .
TextSentencer_T49 9857-10106 Sentence denotes Indeed, because inhibitory receptors are often used by pathogens for immune evasion (as discussed below), immune cells seem to have acquired coactivating receptors later in their evolution than inhibitory receptors, to counterattack these pathogens.
TextSentencer_T49 9857-10106 Sentence denotes Indeed, because inhibitory receptors are often used by pathogens for immune evasion (as discussed below), immune cells seem to have acquired coactivating receptors later in their evolution than inhibitory receptors, to counterattack these pathogens.
TextSentencer_T50 10107-10189 Sentence denotes This model is well represented by the Ly49 paired receptors expressed on NK cells.
TextSentencer_T50 10107-10189 Sentence denotes This model is well represented by the Ly49 paired receptors expressed on NK cells.
TextSentencer_T51 10190-10351 Sentence denotes Inhibitory Ly49 receptors recognise host MHC class I molecules, which can be downregulated on the surface of virus-infected cells, leading to NK cell activation.
TextSentencer_T51 10190-10351 Sentence denotes Inhibitory Ly49 receptors recognise host MHC class I molecules, which can be downregulated on the surface of virus-infected cells, leading to NK cell activation.
TextSentencer_T52 10352-10487 Sentence denotes Mouse cytomegalovirus (MCMV) therefore evades the immune response by producing viral MHC class I-like ligand m157 for inhibitory Ly49I.
TextSentencer_T52 10352-10487 Sentence denotes Mouse cytomegalovirus (MCMV) therefore evades the immune response by producing viral MHC class I-like ligand m157 for inhibitory Ly49I.
TextSentencer_T53 10488-10635 Sentence denotes However, some MCMV-resistant mouse strains also express activating Ly49 receptors, which recognise m157 to directly kill MCMV-infected cells [21] .
TextSentencer_T53 10488-10635 Sentence denotes However, some MCMV-resistant mouse strains also express activating Ly49 receptors, which recognise m157 to directly kill MCMV-infected cells [21] .
TextSentencer_T54 10636-10714 Sentence denotes Still, even in this case it seems that the inhibitory interaction is dominant.
TextSentencer_T54 10636-10714 Sentence denotes Still, even in this case it seems that the inhibitory interaction is dominant.
TextSentencer_T55 10715-10895 Sentence denotes The binding constants determined by Adams et al. using surface plasmon resonance (SPR) were K D = 166 nM for Ly49I/m157 interaction and K D = 1 mM for Ly49H/m157 interaction [22] .
TextSentencer_T55 10715-10895 Sentence denotes The binding constants determined by Adams et al. using surface plasmon resonance (SPR) were K D = 166 nM for Ly49I/m157 interaction and K D = 1 mM for Ly49H/m157 interaction [22] .
TextSentencer_T56 10896-11066 Sentence denotes If activating and inhibitory receptors of a pair interact with the same ligand and inhibition is dominant, when does the coactivating receptor of the pair have an effect?
TextSentencer_T56 10896-11066 Sentence denotes If activating and inhibitory receptors of a pair interact with the same ligand and inhibition is dominant, when does the coactivating receptor of the pair have an effect?
TextSentencer_T57 11067-11260 Sentence denotes Some paired receptors (such as DNAM1 and TIGIT on NK cells [8] ) are expressed constitutively and on the same cell; however, other immune cells only express the coactivating receptor of a pair.
TextSentencer_T57 11067-11260 Sentence denotes Some paired receptors (such as DNAM1 and TIGIT on NK cells [8] ) are expressed constitutively and on the same cell; however, other immune cells only express the coactivating receptor of a pair.
TextSentencer_T58 11261-11396 Sentence denotes For example, mast cells and eosinophils express the coactivating receptor DNAM1 [23] but not its inhibitory receptor counterpart TIGIT.
TextSentencer_T58 11261-11396 Sentence denotes For example, mast cells and eosinophils express the coactivating receptor DNAM1 [23] but not its inhibitory receptor counterpart TIGIT.
TextSentencer_T59 11397-11510 Sentence denotes Interestingly, these effector cells of allergy also express Nectin 2, which is a ligand of TIGIT and DNAM1 [23] .
TextSentencer_T59 11397-11510 Sentence denotes Interestingly, these effector cells of allergy also express Nectin 2, which is a ligand of TIGIT and DNAM1 [23] .
TextSentencer_T60 11511-11769 Sentence denotes The expression by mast cells and eosinophils of only the coactivating receptor and its ligand means that when these cells come together there is enhanced activation, which can explain the self-fuelling, proinflammatory allergic effector unit (AEU) [23, 24] .
TextSentencer_T60 11511-11769 Sentence denotes The expression by mast cells and eosinophils of only the coactivating receptor and its ligand means that when these cells come together there is enhanced activation, which can explain the self-fuelling, proinflammatory allergic effector unit (AEU) [23, 24] .
TextSentencer_T61 11770-11968 Sentence denotes Thus, tissue-resident mast cells start the allergic response and when eosinophils penetrate into the tissue, they interact via soluble mediators and physical binding with mast cells to form the AEU.
TextSentencer_T61 11770-11968 Sentence denotes Thus, tissue-resident mast cells start the allergic response and when eosinophils penetrate into the tissue, they interact via soluble mediators and physical binding with mast cells to form the AEU.
TextSentencer_T62 11969-12156 Sentence denotes This synergistic overactivation of mast cells and eosinophils is an example of the pathology that can be 'lying in wait' when the paired receptors become unbalanced in certain situations.
TextSentencer_T62 11969-12156 Sentence denotes This synergistic overactivation of mast cells and eosinophils is an example of the pathology that can be 'lying in wait' when the paired receptors become unbalanced in certain situations.
TextSentencer_T63 12157-12337 Sentence denotes The paired receptors can be expressed on the same type of immune cell, but not necessarily on the same clone, which enables clonal-dependent activity of the coactivating receptors.
TextSentencer_T63 12157-12337 Sentence denotes The paired receptors can be expressed on the same type of immune cell, but not necessarily on the same clone, which enables clonal-dependent activity of the coactivating receptors.
TextSentencer_T64 12338-12583 Sentence denotes The human killer cell immunoglobulin-like receptors (KIRs) have short or long cytoplasmic domains, with the long forms (such as KIR2DL and KIR3DL) being inhibitory and the short forms (such as KIR2DS and KIR3DS) being activating or coactivating.
TextSentencer_T64 12338-12583 Sentence denotes The human killer cell immunoglobulin-like receptors (KIRs) have short or long cytoplasmic domains, with the long forms (such as KIR2DL and KIR3DL) being inhibitory and the short forms (such as KIR2DS and KIR3DS) being activating or coactivating.
TextSentencer_T65 12584-12744 Sentence denotes They are stochastically expressed on NK cells (some KIR haplotypes have few activating receptors) and thus may function independently on certain NK cell clones.
TextSentencer_T65 12584-12744 Sentence denotes They are stochastically expressed on NK cells (some KIR haplotypes have few activating receptors) and thus may function independently on certain NK cell clones.
TextSentencer_T66 12745-12949 Sentence denotes Similarly, in the case of CD300a and CD300c, which bind phosphatidylserine and phosphatidylethanolamine with opposing effects [25] , NK cells express the members of this receptor pair stochastically [7] .
TextSentencer_T66 12745-12949 Sentence denotes Similarly, in the case of CD300a and CD300c, which bind phosphatidylserine and phosphatidylethanolamine with opposing effects [25] , NK cells express the members of this receptor pair stochastically [7] .
TextSentencer_T67 12950-13098 Sentence denotes In cases where the paired receptors are expressed on the same cell, the spatial expression of the receptors may determine their ability to function.
TextSentencer_T67 12950-13098 Sentence denotes In cases where the paired receptors are expressed on the same cell, the spatial expression of the receptors may determine their ability to function.
TextSentencer_T68 13099-13258 Sentence denotes For example, differential expression of paired receptors in different zones of the NK cell inhibitory and activating synapse [26] can influence their activity.
TextSentencer_T68 13099-13258 Sentence denotes For example, differential expression of paired receptors in different zones of the NK cell inhibitory and activating synapse [26] can influence their activity.
TextSentencer_T69 13259-13384 Sentence denotes The concept of the immune synapse is an important reminder that cells exist in three dimensions and that location is crucial.
TextSentencer_T69 13259-13384 Sentence denotes The concept of the immune synapse is an important reminder that cells exist in three dimensions and that location is crucial.
TextSentencer_T70 13385-13605 Sentence denotes Thus, even if inhibitory and coactivating paired receptors are present on the same cell, they might be segregated into different cellular domains following their gathering at intercellular contacts on the immune synapse.
TextSentencer_T70 13385-13605 Sentence denotes Thus, even if inhibitory and coactivating paired receptors are present on the same cell, they might be segregated into different cellular domains following their gathering at intercellular contacts on the immune synapse.
TextSentencer_T71 13606-13747 Sentence denotes These domains are sometimes associated with different signalling molecules and, in such situations, the coactivating receptor might function.
TextSentencer_T71 13606-13747 Sentence denotes These domains are sometimes associated with different signalling molecules and, in such situations, the coactivating receptor might function.
TextSentencer_T72 13748-13891 Sentence denotes The level of expression (number and density) of inhibitory and coactivating members of the paired receptors might also affect their activities.
TextSentencer_T72 13748-13891 Sentence denotes The level of expression (number and density) of inhibitory and coactivating members of the paired receptors might also affect their activities.
TextSentencer_T73 13892-14074 Sentence denotes Indeed, although inhibitory receptors have overall a higher affinity for their ligand, they may be present at lower densities at the cell surface than their coactivating counterpart.
TextSentencer_T73 13892-14074 Sentence denotes Indeed, although inhibitory receptors have overall a higher affinity for their ligand, they may be present at lower densities at the cell surface than their coactivating counterpart.
TextSentencer_T74 14075-14312 Sentence denotes Therefore, in the context of target cells expressing a low level of the common ligand, the inhibitory receptors will engage ligand first, thus preventing engagement of the activating counterpart, which will lead to a dominant inhibition.
TextSentencer_T74 14075-14312 Sentence denotes Therefore, in the context of target cells expressing a low level of the common ligand, the inhibitory receptors will engage ligand first, thus preventing engagement of the activating counterpart, which will lead to a dominant inhibition.
TextSentencer_T75 14313-14602 Sentence denotes By contrast, in the context of a target cell expressing high levels of the ligand, the activating receptors will also be engaged and owing to their greater density at the cell surface of the responding cells compared with the inhibitory receptors, the dominant response will be activation.
TextSentencer_T75 14313-14602 Sentence denotes By contrast, in the context of a target cell expressing high levels of the ligand, the activating receptors will also be engaged and owing to their greater density at the cell surface of the responding cells compared with the inhibitory receptors, the dominant response will be activation.
TextSentencer_T76 14603-14694 Sentence denotes Finally, paired receptors can be expressed on the same cells, but at different time points.
TextSentencer_T76 14603-14694 Sentence denotes Finally, paired receptors can be expressed on the same cells, but at different time points.
TextSentencer_T77 14695-14821 Sentence denotes A wellcharacterised example is that of CD28 and cytotoxic T lymphocyte antigen (CTLA)4; both of which bind CD80 and CD86 [6] .
TextSentencer_T77 14695-14821 Sentence denotes A wellcharacterised example is that of CD28 and cytotoxic T lymphocyte antigen (CTLA)4; both of which bind CD80 and CD86 [6] .
TextSentencer_T78 14822-15044 Sentence denotes The activity of immature T cells is well controlled by a rigorous education process in the thymus, but the later stages of T cell activity in the periphery must be checked as well, and this is achieved by paired receptors.
TextSentencer_T78 14822-15044 Sentence denotes The activity of immature T cells is well controlled by a rigorous education process in the thymus, but the later stages of T cell activity in the periphery must be checked as well, and this is achieved by paired receptors.
TextSentencer_T79 15045-15209 Sentence denotes The coactivating receptor CD28 is expressed on naïve T cells, which allows them to respond to signals presented by a dendritic cell (DC) that has sensed a pathogen.
TextSentencer_T79 15045-15209 Sentence denotes The coactivating receptor CD28 is expressed on naïve T cells, which allows them to respond to signals presented by a dendritic cell (DC) that has sensed a pathogen.
TextSentencer_T80 15210-15289 Sentence denotes These naïve T cells, however, do not yet express the inhibitory receptor CTLA4.
TextSentencer_T80 15210-15289 Sentence denotes These naïve T cells, however, do not yet express the inhibitory receptor CTLA4.
TextSentencer_T81 15290-15372 Sentence denotes Expression of CTLA4 by conventional T cells occurs only after TCR activation [6] .
TextSentencer_T81 15290-15372 Sentence denotes Expression of CTLA4 by conventional T cells occurs only after TCR activation [6] .
TextSentencer_T82 15373-15569 Sentence denotes Once it is expressed, CTLA4 can inhibit T cell activity by various mechanisms, including direct signalling, competing for ligands and even 'grabbing' and degrading ligands from target cells [27] .
TextSentencer_T82 15373-15569 Sentence denotes Once it is expressed, CTLA4 can inhibit T cell activity by various mechanisms, including direct signalling, competing for ligands and even 'grabbing' and degrading ligands from target cells [27] .
TextSentencer_T83 15570-15859 Sentence denotes As a result of the higher affinity of inhibitory receptors for their ligand, paired receptors seem to provide a balanced form of inhibition under homeostatic conditions, by which inactivity is favoured by this group of receptors and thereby by a large part of the immune system as a whole.
TextSentencer_T83 15570-15859 Sentence denotes As a result of the higher affinity of inhibitory receptors for their ligand, paired receptors seem to provide a balanced form of inhibition under homeostatic conditions, by which inactivity is favoured by this group of receptors and thereby by a large part of the immune system as a whole.
TextSentencer_T84 15860-16108 Sentence denotes This enables T and NK cells harbouring cytolytic granulesand mast cells containing granules with proinflammatory mediatorsnot to harm normal tissues, but still respond quickly through the already present coactivating receptors when there is danger.
TextSentencer_T84 15860-16108 Sentence denotes This enables T and NK cells harbouring cytolytic granulesand mast cells containing granules with proinflammatory mediatorsnot to harm normal tissues, but still respond quickly through the already present coactivating receptors when there is danger.
TextSentencer_T85 16109-16291 Sentence denotes The simultaneous presence of inhibitory and coactivating receptors also keeps immune cells in a responsive state that allows them to detect small variations within their environment.
TextSentencer_T85 16109-16291 Sentence denotes The simultaneous presence of inhibitory and coactivating receptors also keeps immune cells in a responsive state that allows them to detect small variations within their environment.
TextSentencer_T86 16292-16489 Sentence denotes For example, NK cells, in the absence of MHC class I are hyporesponsive, which indicates that inhibitory receptor signalling might be involved in the education and responsiveness of NK cells [28] .
TextSentencer_T86 16292-16489 Sentence denotes For example, NK cells, in the absence of MHC class I are hyporesponsive, which indicates that inhibitory receptor signalling might be involved in the education and responsiveness of NK cells [28] .
TextSentencer_T87 16490-16710 Sentence denotes It has also been proposed that chronic activating receptor signals, that are delivered in the absence of inhibition, desensitize NK cells, leading to their hyporesponsiveness, by a process referred to as disarming [29] .
TextSentencer_T87 16490-16710 Sentence denotes It has also been proposed that chronic activating receptor signals, that are delivered in the absence of inhibition, desensitize NK cells, leading to their hyporesponsiveness, by a process referred to as disarming [29] .
TextSentencer_T88 16711-16839 Sentence denotes Thus, paired coactivating and inhibitory receptors might coexist to fine tune the response of immune cells to their environment.
TextSentencer_T88 16711-16839 Sentence denotes Thus, paired coactivating and inhibitory receptors might coexist to fine tune the response of immune cells to their environment.
TextSentencer_T89 16840-17124 Sentence denotes This ensures that under homeostatic conditions, cells remain quiescent, but still functional, and upon subtle but rapid changes in the environment (e.g., an increase in ligand density, providing additional ligands for activating receptors) these cells are able to respond efficiently.
TextSentencer_T89 16840-17124 Sentence denotes This ensures that under homeostatic conditions, cells remain quiescent, but still functional, and upon subtle but rapid changes in the environment (e.g., an increase in ligand density, providing additional ligands for activating receptors) these cells are able to respond efficiently.
TextSentencer_T90 17125-17472 Sentence denotes This theory is directly related to the discontinuity theory that has been postulated by Vivier and colleagues, which proposes that immune cells generate an effector response when there is a discontinuity, that is, sudden changes in antigenic stimulation, whereas they tend to become tolerant to continuously (slow or continuous stimulation) [30] .
TextSentencer_T90 17125-17472 Sentence denotes This theory is directly related to the discontinuity theory that has been postulated by Vivier and colleagues, which proposes that immune cells generate an effector response when there is a discontinuity, that is, sudden changes in antigenic stimulation, whereas they tend to become tolerant to continuously (slow or continuous stimulation) [30] .
TextSentencer_T91 17473-17542 Sentence denotes The variety of shared ligands for the paired receptors is impressive.
TextSentencer_T91 17473-17542 Sentence denotes The variety of shared ligands for the paired receptors is impressive.
TextSentencer_T92 17543-17655 Sentence denotes Paired receptors recognise everything from proteins to sugars, to lipids, to nucleic acids ( [31] and Table 1 ).
TextSentencer_T92 17543-17655 Sentence denotes Paired receptors recognise everything from proteins to sugars, to lipids, to nucleic acids ( [31] and Table 1 ).
TextSentencer_T93 17656-17836 Sentence denotes This vast diversity of potential ligands indicates that they might be involved in a large number of immune responses and clinical situations, many of which remain to be discovered.
TextSentencer_T93 17656-17836 Sentence denotes This vast diversity of potential ligands indicates that they might be involved in a large number of immune responses and clinical situations, many of which remain to be discovered.
TextSentencer_T94 17837-17926 Sentence denotes Many of the shared ligands are ubiquitously expressed under normal conditions (Table 1 ).
TextSentencer_T94 17837-17926 Sentence denotes Many of the shared ligands are ubiquitously expressed under normal conditions (Table 1 ).
TextSentencer_T95 17927-18119 Sentence denotes This may represent the role of paired receptors as a basic method of immune homeostasis, with healthy tissues constantly beingsensed by thepaired receptorsso that immune responses aredampened.
TextSentencer_T95 17927-18119 Sentence denotes This may represent the role of paired receptors as a basic method of immune homeostasis, with healthy tissues constantly beingsensed by thepaired receptorsso that immune responses aredampened.
TextSentencer_T96 18120-18405 Sentence denotes Pathogens are also sensed by the paired receptors; for example, the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) short (CEACAM1-S) and long (CEA-CAM1-L) isoforms recognise a particularly large set of pathogen ligands of different viruses and bacteria (Table 1 ).
TextSentencer_T96 18120-18405 Sentence denotes Pathogens are also sensed by the paired receptors; for example, the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) short (CEACAM1-S) and long (CEA-CAM1-L) isoforms recognise a particularly large set of pathogen ligands of different viruses and bacteria (Table 1 ).
TextSentencer_T97 18406-18486 Sentence denotes In many cases, virus recognition by paired receptors is beneficial to the virus.
TextSentencer_T97 18406-18486 Sentence denotes In many cases, virus recognition by paired receptors is beneficial to the virus.
TextSentencer_T98 18487-18625 Sentence denotes For example, CD300a facilitates the infection of several mosquito-borne viruses including Dengue, West Nile and Chikungunya viruses [32] .
TextSentencer_T98 18487-18625 Sentence denotes For example, CD300a facilitates the infection of several mosquito-borne viruses including Dengue, West Nile and Chikungunya viruses [32] .
TextSentencer_T99 18626-18764 Sentence denotes In addition, the K14 protein of human herpesvirus 8 mimics CD200 in downregulating macrophage activation through the CD200 receptor [33] .
TextSentencer_T99 18626-18764 Sentence denotes In addition, the K14 protein of human herpesvirus 8 mimics CD200 in downregulating macrophage activation through the CD200 receptor [33] .
TextSentencer_T100 18765-18888 Sentence denotes Interestingly, the coactivating CD200 receptors were mainly described in mice and do not show substantial binding to CD200.
TextSentencer_T100 18765-18888 Sentence denotes Interestingly, the coactivating CD200 receptors were mainly described in mice and do not show substantial binding to CD200.
TextSentencer_T101 18889-18984 Sentence denotes Expression of the cellular ligands for the paired receptors can also be modulated by pathogens.
TextSentencer_T101 18889-18984 Sentence denotes Expression of the cellular ligands for the paired receptors can also be modulated by pathogens.
TextSentencer_T102 18985-19233 Sentence denotes For example, the cell surface expression of CEACAM1, which binds homophilically to the paired receptors CEACAM1-L and CEACAM1-S expressed on effector cells, is upregulated on the infected target cells following infection with several viruses [34] .
TextSentencer_T102 18985-19233 Sentence denotes For example, the cell surface expression of CEACAM1, which binds homophilically to the paired receptors CEACAM1-L and CEACAM1-S expressed on effector cells, is upregulated on the infected target cells following infection with several viruses [34] .
TextSentencer_T103 19234-19430 Sentence denotes Cellular transformation can also lead to the upregulation of ligands for the paired receptors; for example, expression of PVR (a TIGIT and DNAM1 ligand) is upregulated in many solid tumours [35] .
TextSentencer_T103 19234-19430 Sentence denotes Cellular transformation can also lead to the upregulation of ligands for the paired receptors; for example, expression of PVR (a TIGIT and DNAM1 ligand) is upregulated in many solid tumours [35] .
TextSentencer_T104 19431-19770 Sentence denotes Finally, some ligands such as phosphatidylserine and phosphatidylethanolamine that are normally expressed on the cell surface following apoptosis and are recognised by CD300a and CD300c, can be upregulated, even in the absence of apoptosis, following viral infection, malignant transformation [25] , and in allergic inflammation [36, 37] .
TextSentencer_T104 19431-19770 Sentence denotes Finally, some ligands such as phosphatidylserine and phosphatidylethanolamine that are normally expressed on the cell surface following apoptosis and are recognised by CD300a and CD300c, can be upregulated, even in the absence of apoptosis, following viral infection, malignant transformation [25] , and in allergic inflammation [36, 37] .
TextSentencer_T105 19771-19819 Sentence denotes The underlying mechanism is not well understood.
TextSentencer_T105 19771-19819 Sentence denotes The underlying mechanism is not well understood.
TextSentencer_T106 19820-20044 Sentence denotes As discussed below, as inhibition is the dominant response of paired receptors, pathogens and tumours will benefit from upregulating the cellular ligands of the paired receptors to protect themselves from immune cell attack.
TextSentencer_T106 19820-20044 Sentence denotes As discussed below, as inhibition is the dominant response of paired receptors, pathogens and tumours will benefit from upregulating the cellular ligands of the paired receptors to protect themselves from immune cell attack.
TextSentencer_T107 20045-20199 Sentence denotes A wide variety of pathogens use the shared ligands of the paired receptors as their cellular adhesion or entry receptors (see Table 2 for virus examples).
TextSentencer_T107 20045-20199 Sentence denotes A wide variety of pathogens use the shared ligands of the paired receptors as their cellular adhesion or entry receptors (see Table 2 for virus examples).
TextSentencer_T108 20200-20291 Sentence denotes In particular, sialic acids are used widely as adhesion and/or entry receptors for viruses.
TextSentencer_T108 20200-20291 Sentence denotes In particular, sialic acids are used widely as adhesion and/or entry receptors for viruses.
TextSentencer_T109 20292-20452 Sentence denotes It is possible that the ubiquitous expression of sialic acids makes them an attractive target as viruses can adhere to and thereafter invade many types of cell.
TextSentencer_T109 20292-20452 Sentence denotes It is possible that the ubiquitous expression of sialic acids makes them an attractive target as viruses can adhere to and thereafter invade many types of cell.
TextSentencer_T110 20453-20556 Sentence denotes Other paired receptor ligands that are used as entry receptors for viruses are not as widely expressed.
TextSentencer_T110 20453-20556 Sentence denotes Other paired receptor ligands that are used as entry receptors for viruses are not as widely expressed.
TextSentencer_T111 20557-20654 Sentence denotes A classic example is PVR, which was discovered for its role as the entry receptor for poliovirus.
TextSentencer_T111 20557-20654 Sentence denotes A classic example is PVR, which was discovered for its role as the entry receptor for poliovirus.
TextSentencer_T112 20655-20746 Sentence denotes Years later, it was shown that PVR binds the paired receptors DNAM1 and TIGIT [8, 38, 39] .
TextSentencer_T112 20655-20746 Sentence denotes Years later, it was shown that PVR binds the paired receptors DNAM1 and TIGIT [8, 38, 39] .
TextSentencer_T113 20747-20870 Sentence denotes PVR is also a ligand for CD96 [40] , although it is unclear whether this receptor has an inhibitory or activating function.
TextSentencer_T113 20747-20870 Sentence denotes PVR is also a ligand for CD96 [40] , although it is unclear whether this receptor has an inhibitory or activating function.
TextSentencer_T114 20871-20940 Sentence denotes Bacteria can also use the paired receptor ligands as entry receptors.
TextSentencer_T114 20871-20940 Sentence denotes Bacteria can also use the paired receptor ligands as entry receptors.
TextSentencer_T115 20941-21090 Sentence denotes For example, Helicobacter pylori binds CEACAM1 using its HopQ protein to facilitate translocation of its virulent protein CagA into host cells [41] .
TextSentencer_T115 20941-21090 Sentence denotes For example, Helicobacter pylori binds CEACAM1 using its HopQ protein to facilitate translocation of its virulent protein CagA into host cells [41] .
TextSentencer_T116 21091-21224 Sentence denotes This is of particular clinical importance as CagA has been implicated in the promotion of gastric cancer and other pathologies [42] .
TextSentencer_T116 21091-21224 Sentence denotes This is of particular clinical importance as CagA has been implicated in the promotion of gastric cancer and other pathologies [42] .
TextSentencer_T117 21225-21572 Sentence denotes Altogether, given what we know about the functions of paired receptors in the immune system, there is a great deal of evolutionary sense behind the use of shared ligands as entry receptors, especially since is seems as if the inhibitory receptors of the paired receptors were developed prior to the development of the activating ones (Figure 2A ).
TextSentencer_T117 21225-21572 Sentence denotes Altogether, given what we know about the functions of paired receptors in the immune system, there is a great deal of evolutionary sense behind the use of shared ligands as entry receptors, especially since is seems as if the inhibitory receptors of the paired receptors were developed prior to the development of the activating ones (Figure 2A ).
TextSentencer_T118 21573-21759 Sentence denotes The expression of shared ligands may shield the invading pathogens during the early stages of cellular infection, where they are generally more vulnerable to elimination by immune cells.
TextSentencer_T118 21573-21759 Sentence denotes The expression of shared ligands may shield the invading pathogens during the early stages of cellular infection, where they are generally more vulnerable to elimination by immune cells.
TextSentencer_T119 21760-21965 Sentence denotes In addition, the baseline immuneinhibitory property of a cell expressing shared ligands also means that there is a lag period before the cell can be tipped towards an immune-activating state ( Figure 2B ).
TextSentencer_T119 21760-21965 Sentence denotes In addition, the baseline immuneinhibitory property of a cell expressing shared ligands also means that there is a lag period before the cell can be tipped towards an immune-activating state ( Figure 2B ).
TextSentencer_T120 21966-22129 Sentence denotes This would allow the pathogen to proliferate more, reaching higher numbers and thus increasing its chances of surviving immune attack when it starts ( Figure 2B ).
TextSentencer_T120 21966-22129 Sentence denotes This would allow the pathogen to proliferate more, reaching higher numbers and thus increasing its chances of surviving immune attack when it starts ( Figure 2B ).
TextSentencer_T121 22130-22282 Sentence denotes Using a shared ligand as an entry receptor ensures these benefits, and provides the pathogen with a distinct advantage in outperforming immune pressure.
TextSentencer_T121 22130-22282 Sentence denotes Using a shared ligand as an entry receptor ensures these benefits, and provides the pathogen with a distinct advantage in outperforming immune pressure.
TextSentencer_T122 22283-22459 Sentence denotes However, that pathogens use ligands for paired receptors as their entry receptors might be viewed as risky because the ligand can also be recognised by a coactivating receptor.
TextSentencer_T122 22283-22459 Sentence denotes However, that pathogens use ligands for paired receptors as their entry receptors might be viewed as risky because the ligand can also be recognised by a coactivating receptor.
TextSentencer_T123 22460-22598 Sentence denotes Thus, we hypothesise that some pathogens will target the inhibitory receptor of the pair to further inhibit and escape immune recognition.
TextSentencer_T123 22460-22598 Sentence denotes Thus, we hypothesise that some pathogens will target the inhibitory receptor of the pair to further inhibit and escape immune recognition.
TextSentencer_T124 22599-22700 Sentence denotes Indeed, as mentioned above some viruses and bacteria directly target the paired receptors themselves.
TextSentencer_T124 22599-22700 Sentence denotes Indeed, as mentioned above some viruses and bacteria directly target the paired receptors themselves.
TextSentencer_T125 22701-22930 Sentence denotes Invading a host cell that sends an inhibitory signal to immune cells allows pathogens more time to replicate safely. (Ba) A host cell sends no net signal to the immune system at the initiation of the pathological process (t = 0).
TextSentencer_T125 22701-22930 Sentence denotes Invading a host cell that sends an inhibitory signal to immune cells allows pathogens more time to replicate safely. (Ba) A host cell sends no net signal to the immune system at the initiation of the pathological process (t = 0).
TextSentencer_T126 22931-23071 Sentence denotes This is true of several cell types, such as beta cells in the pancreas as well as some cells in immune privileged sites throughout the body.
TextSentencer_T126 22931-23071 Sentence denotes This is true of several cell types, such as beta cells in the pancreas as well as some cells in immune privileged sites throughout the body.
TextSentencer_T127 23072-23467 Sentence denotes The time that the host cell takes to produce a signal that is sufficient to activate immune cells is termed t A . (Bb) If the host cell sends an inhibitory signal to the immune system at baseline (through its expression of a shared ligand), then the same processes that induce immune-activating signals will take longer to cross the threshold required to activate the immune system (t B > t A ).
TextSentencer_T127 23072-23467 Sentence denotes The time that the host cell takes to produce a signal that is sufficient to activate immune cells is termed t A . (Bb) If the host cell sends an inhibitory signal to the immune system at baseline (through its expression of a shared ligand), then the same processes that induce immune-activating signals will take longer to cross the threshold required to activate the immune system (t B > t A ).
TextSentencer_T128 23468-23624 Sentence denotes This lag period (t B À t A ) allows for greater viral replication and increased pathology to develop before immune intervention (blue portion of the graph).
TextSentencer_T128 23468-23624 Sentence denotes This lag period (t B À t A ) allows for greater viral replication and increased pathology to develop before immune intervention (blue portion of the graph).
TextSentencer_T129 23625-23702 Sentence denotes In turn, the larger viral population is more likely to survive immune attack.
TextSentencer_T129 23625-23702 Sentence denotes In turn, the larger viral population is more likely to survive immune attack.
TextSentencer_T130 23703-23773 Sentence denotes Onset of immunopathology is indicated by the red portion of the graph.
TextSentencer_T130 23703-23773 Sentence denotes Onset of immunopathology is indicated by the red portion of the graph.
TextSentencer_T131 23774-23997 Sentence denotes An example of a bacterial pathogen that targets paired receptors is Fusobacterium nucleatum, which uses its Fap2 protein to bind TIGIT only (and not its coactivating partner DNAM1) and inhibits immune cell activities [43] .
TextSentencer_T131 23774-23997 Sentence denotes An example of a bacterial pathogen that targets paired receptors is Fusobacterium nucleatum, which uses its Fap2 protein to bind TIGIT only (and not its coactivating partner DNAM1) and inhibits immune cell activities [43] .
TextSentencer_T132 23998-24250 Sentence denotes Given that viruses use ligands of the paired receptors as entry proteins and that tumours can upregulate the expression of paired receptor ligands to inhibit immune cell activity, it is possible that viruses can be used for tumour therapeutic purposes.
TextSentencer_T132 23998-24250 Sentence denotes Given that viruses use ligands of the paired receptors as entry proteins and that tumours can upregulate the expression of paired receptor ligands to inhibit immune cell activity, it is possible that viruses can be used for tumour therapeutic purposes.
TextSentencer_T133 24251-24477 Sentence denotes If a specific type of cancer overexpresses a shared ligandfor example, PVR in pancreatic cancer [35] then a virus that uses the same shared ligand as an entry receptor and that can lyse the cells could be used therapeutically.
TextSentencer_T133 24251-24477 Sentence denotes If a specific type of cancer overexpresses a shared ligandfor example, PVR in pancreatic cancer [35] then a virus that uses the same shared ligand as an entry receptor and that can lyse the cells could be used therapeutically.
TextSentencer_T134 24478-24634 Sentence denotes In the case of pancreatic cancer, a poliovirus strain that is engineered to be oncolytic [44] could prove useful in combating this otherwise lethal disease.
TextSentencer_T134 24478-24634 Sentence denotes In the case of pancreatic cancer, a poliovirus strain that is engineered to be oncolytic [44] could prove useful in combating this otherwise lethal disease.
TextSentencer_T135 24635-24883 Sentence denotes This idea is particularly attractive given the fact that patients with pancreatic cancer who have higher expression levels of PVR (and would therefore potentially be more responsive to oncolytic viral therapy) currently have poorer prognoses [35] .
TextSentencer_T135 24635-24883 Sentence denotes This idea is particularly attractive given the fact that patients with pancreatic cancer who have higher expression levels of PVR (and would therefore potentially be more responsive to oncolytic viral therapy) currently have poorer prognoses [35] .
TextSentencer_T136 24884-25007 Sentence denotes Using this strategy, immune evasion, which is critical for cancer cell survival, may turn out to be a targetable weak spot.
TextSentencer_T136 24884-25007 Sentence denotes Using this strategy, immune evasion, which is critical for cancer cell survival, may turn out to be a targetable weak spot.
TextSentencer_T137 25008-25150 Sentence denotes Antibodies against checkpoint receptors such as anti-PD1 (Keytruda) are currently very successfully used for the treatment of various tumours.
TextSentencer_T137 25008-25150 Sentence denotes Antibodies against checkpoint receptors such as anti-PD1 (Keytruda) are currently very successfully used for the treatment of various tumours.
TextSentencer_T138 25151-25427 Sentence denotes Similarly, using an array of agonistic, antagonistic, and bispecific antibodies against the paired receptors (which are difficult to obtain due to the high resemblance of their extracellular portions), it is possible to tip the balance of the immune response in any direction.
TextSentencer_T138 25151-25427 Sentence denotes Similarly, using an array of agonistic, antagonistic, and bispecific antibodies against the paired receptors (which are difficult to obtain due to the high resemblance of their extracellular portions), it is possible to tip the balance of the immune response in any direction.
TextSentencer_T139 25428-25684 Sentence denotes Agonism of a coactivating receptor or antagonism of an inhibitory receptor of the paired receptors could encourage the immune system to fight off pathogens or cancer; the converse response could be used to treat a range of autoimmune disorders and allergy.
TextSentencer_T139 25428-25684 Sentence denotes Agonism of a coactivating receptor or antagonism of an inhibitory receptor of the paired receptors could encourage the immune system to fight off pathogens or cancer; the converse response could be used to treat a range of autoimmune disorders and allergy.
TextSentencer_T140 25685-25802 Sentence denotes Phase I trials are already underway examining the use of a TIGIT-blocking antibody in the treatment of solid tumours.
TextSentencer_T140 25685-25802 Sentence denotes Phase I trials are already underway examining the use of a TIGIT-blocking antibody in the treatment of solid tumours.
TextSentencer_T141 25803-25971 Sentence denotes Bispecific antibodies could be used to help their homing to the correct cell types, and to avoid some of the side effects that are associated with biological therapies.
TextSentencer_T141 25803-25971 Sentence denotes Bispecific antibodies could be used to help their homing to the correct cell types, and to avoid some of the side effects that are associated with biological therapies.
TextSentencer_T142 25972-26185 Sentence denotes For example, we previously generated a bispecific antibody targeting the CC chemokine receptor 3, that preferentially recognises this receptor on mouse eosinophils, and the inhibitory paired receptor CD300a [45] .
TextSentencer_T142 25972-26185 Sentence denotes For example, we previously generated a bispecific antibody targeting the CC chemokine receptor 3, that preferentially recognises this receptor on mouse eosinophils, and the inhibitory paired receptor CD300a [45] .
TextSentencer_T143 26186-26309 Sentence denotes This antibody was used in a mouse model of asthma and showed efficacy in reducing eosinophilia and lung inflammation [45] .
TextSentencer_T143 26186-26309 Sentence denotes This antibody was used in a mouse model of asthma and showed efficacy in reducing eosinophilia and lung inflammation [45] .
TextSentencer_T144 26310-26404 Sentence denotes Similarly, we developed a bispecific antibody that targets IgE and CD300a on mast cells [37] .
TextSentencer_T144 26310-26404 Sentence denotes Similarly, we developed a bispecific antibody that targets IgE and CD300a on mast cells [37] .
TextSentencer_T145 26405-26551 Sentence denotes Given the extensive involvement of paired receptors in different processes, similar antibody-based strategies could be tested in various diseases.
TextSentencer_T145 26405-26551 Sentence denotes Given the extensive involvement of paired receptors in different processes, similar antibody-based strategies could be tested in various diseases.
TextSentencer_T146 26552-26637 Sentence denotes MHC molecules are involved in education processes of both T cells and NK cells [46] .
TextSentencer_T146 26552-26637 Sentence denotes MHC molecules are involved in education processes of both T cells and NK cells [46] .
TextSentencer_T147 26638-26714 Sentence denotes MHC molecules are important in regulating the strength of T cell reactivity.
TextSentencer_T147 26638-26714 Sentence denotes MHC molecules are important in regulating the strength of T cell reactivity.
TextSentencer_T148 26715-26832 Sentence denotes A too strong or a too weak signal will lead to deletion of a T cell clone during the course of the education process.
TextSentencer_T148 26715-26832 Sentence denotes A too strong or a too weak signal will lead to deletion of a T cell clone during the course of the education process.
TextSentencer_T149 26833-27019 Sentence denotes As the paired receptors are also balanced, immune cells might be educated via the interaction of the shared receptors with their shared ligands, as was recently shown for NK cells [47] .
TextSentencer_T149 26833-27019 Sentence denotes As the paired receptors are also balanced, immune cells might be educated via the interaction of the shared receptors with their shared ligands, as was recently shown for NK cells [47] .
TextSentencer_T150 27020-27094 Sentence denotes In this review, we examine the paired receptors from several perspectives.
TextSentencer_T150 27020-27094 Sentence denotes In this review, we examine the paired receptors from several perspectives.
TextSentencer_T151 27095-27240 Sentence denotes The curious phenomenon of two receptors sharing a ligand but having opposite effects on immune cells has exceptionally far-reaching consequences.
TextSentencer_T151 27095-27240 Sentence denotes The curious phenomenon of two receptors sharing a ligand but having opposite effects on immune cells has exceptionally far-reaching consequences.
TextSentencer_T152 27241-27349 Sentence denotes We describe that this is essentially a form of carefully balanced inhibition because inhibition is dominant.
TextSentencer_T152 27241-27349 Sentence denotes We describe that this is essentially a form of carefully balanced inhibition because inhibition is dominant.
TextSentencer_T153 27350-27580 Sentence denotes We propose that the paired receptors are sometimes not truly paired and that they can be separated temporally and/or clonally, or sometimes being uncoupled in the even when expressed on the same cell, in the immunological synapse.
TextSentencer_T153 27350-27580 Sentence denotes We propose that the paired receptors are sometimes not truly paired and that they can be separated temporally and/or clonally, or sometimes being uncoupled in the even when expressed on the same cell, in the immunological synapse.
TextSentencer_T154 27581-27665 Sentence denotes This enables the co-stimulating partner of the pair to be active in some situations.
TextSentencer_T154 27581-27665 Sentence denotes This enables the co-stimulating partner of the pair to be active in some situations.
TextSentencer_T155 27666-27722 Sentence denotes Do additional paired receptors and paired ligands exist?
TextSentencer_T155 27666-27722 Sentence denotes Do additional paired receptors and paired ligands exist?
TextSentencer_T156 27723-27796 Sentence denotes What are the mechanisms controlling the expression of the paired ligands?
TextSentencer_T156 27723-27796 Sentence denotes What are the mechanisms controlling the expression of the paired ligands?
TextSentencer_T157 27797-27931 Sentence denotes Better understanding of the regulation of the paired ligand expression is also critical to understand the biology of paired receptors.
TextSentencer_T157 27797-27931 Sentence denotes Better understanding of the regulation of the paired ligand expression is also critical to understand the biology of paired receptors.
TextSentencer_T158 27932-28076 Sentence denotes Are paired receptors involved in the education of additional immune cell subsets, other than NK cells, for example of mast cells or eosinophils?
TextSentencer_T158 27932-28076 Sentence denotes Are paired receptors involved in the education of additional immune cell subsets, other than NK cells, for example of mast cells or eosinophils?
TextSentencer_T159 28077-28214 Sentence denotes Can pathogens affect the expression of the paired receptors and enhance the expression of the inhibitory partner to escape immune attack?
TextSentencer_T159 28077-28214 Sentence denotes Can pathogens affect the expression of the paired receptors and enhance the expression of the inhibitory partner to escape immune attack?
TextSentencer_T160 28215-28332 Sentence denotes Can the expression of the paired receptors and their ligands be manipulated for therapy against cancer and pathogens?
TextSentencer_T160 28215-28332 Sentence denotes Can the expression of the paired receptors and their ligands be manipulated for therapy against cancer and pathogens?
TextSentencer_T161 28333-28446 Sentence denotes Will paired receptors be found and function in pathogens and in nonimmune cells and if so, what is their purpose?
TextSentencer_T161 28333-28446 Sentence denotes Will paired receptors be found and function in pathogens and in nonimmune cells and if so, what is their purpose?
TextSentencer_T162 28447-28536 Sentence denotes The biochemically diverse shared ligands of the paired receptors are no less fascinating.
TextSentencer_T162 28447-28536 Sentence denotes The biochemically diverse shared ligands of the paired receptors are no less fascinating.
TextSentencer_T163 28537-28631 Sentence denotes Some ligands are upregulated in various pathologies, or are used by pathogens to infect cells.
TextSentencer_T163 28537-28631 Sentence denotes Some ligands are upregulated in various pathologies, or are used by pathogens to infect cells.
TextSentencer_T164 28632-28828 Sentence denotes We hypothesise that using the shared ligands as entry or adhesion receptors is beneficial for pathogens because it better protects them from immune attack (as inhibition is the dominant response).
TextSentencer_T164 28632-28828 Sentence denotes We hypothesise that using the shared ligands as entry or adhesion receptors is beneficial for pathogens because it better protects them from immune attack (as inhibition is the dominant response).
TextSentencer_T165 28829-28967 Sentence denotes We suggest that we can use this property to generate oncolytic viruses that could be used to treat tumours that upregulate shared ligands.
TextSentencer_T165 28829-28967 Sentence denotes We suggest that we can use this property to generate oncolytic viruses that could be used to treat tumours that upregulate shared ligands.
TextSentencer_T166 28968-29108 Sentence denotes Furthermore, we hypothesise that some pathogens target the inhibitory receptor of the pair to further inhibit and escape immune recognition.
TextSentencer_T166 28968-29108 Sentence denotes Furthermore, we hypothesise that some pathogens target the inhibitory receptor of the pair to further inhibit and escape immune recognition.
TextSentencer_T167 29109-29206 Sentence denotes We also propose that the paired receptors might be involved in education of various immune cells.
TextSentencer_T167 29109-29206 Sentence denotes We also propose that the paired receptors might be involved in education of various immune cells.
TextSentencer_T168 29207-29368 Sentence denotes Looking at the paired receptors as a whole, and understanding the intricacy of this system in both health and disease may prove useful for clinical applications.
TextSentencer_T168 29207-29368 Sentence denotes Looking at the paired receptors as a whole, and understanding the intricacy of this system in both health and disease may prove useful for clinical applications.
TextSentencer_T169 29369-29507 Sentence denotes These receptors have already been linked to many immunological processes, and many more roles await discovery (see Outstanding Questions).
TextSentencer_T169 29369-29507 Sentence denotes These receptors have already been linked to many immunological processes, and many more roles await discovery (see Outstanding Questions).
TextSentencer_T170 29508-29689 Sentence denotes Immunotherapy has undergone great improvements in the past few years, and we hope that understanding of the function of paired receptors will continue to contribute to this success.
TextSentencer_T170 29508-29689 Sentence denotes Immunotherapy has undergone great improvements in the past few years, and we hope that understanding of the function of paired receptors will continue to contribute to this success.