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LitCovid-PD-FMA-UBERON

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LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T18","span":{"begin":903,"end":914},"obj":"Phenotype"},{"id":"T19","span":{"begin":1141,"end":1152},"obj":"Phenotype"},{"id":"T20","span":{"begin":2884,"end":2889},"obj":"Phenotype"},{"id":"T21","span":{"begin":3056,"end":3081},"obj":"Phenotype"},{"id":"T22","span":{"begin":3161,"end":3172},"obj":"Phenotype"},{"id":"T23","span":{"begin":4833,"end":4844},"obj":"Phenotype"},{"id":"T24","span":{"begin":10204,"end":10223},"obj":"Phenotype"},{"id":"T25","span":{"begin":10255,"end":10284},"obj":"Phenotype"},{"id":"T26","span":{"begin":10387,"end":10393},"obj":"Phenotype"},{"id":"T27","span":{"begin":10854,"end":10863},"obj":"Phenotype"}],"attributes":[{"id":"A18","pred":"hp_id","subj":"T18","obj":"http://purl.obolibrary.org/obo/HP_0001888"},{"id":"A19","pred":"hp_id","subj":"T19","obj":"http://purl.obolibrary.org/obo/HP_0001888"},{"id":"A20","pred":"hp_id","subj":"T20","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A21","pred":"hp_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/HP_0005403"},{"id":"A22","pred":"hp_id","subj":"T22","obj":"http://purl.obolibrary.org/obo/HP_0001888"},{"id":"A23","pred":"hp_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/HP_0001888"},{"id":"A24","pred":"hp_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/HP_0002960"},{"id":"A25","pred":"hp_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/HP_0005681"},{"id":"A26","pred":"hp_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/HP_0100806"},{"id":"A27","pred":"hp_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/HP_0002090"}],"text":"T Cell Responses\nT cells play a fundamental role in viral infections: CD4 T cells provide B cell help for antibody production and orchestrate the response of other immune cells, whereas CD8 T cells kill infected cells to reduce the viral burden. However, dysregulated T cell responses can result in immunopathology. To better understand the role of T cell responses in SARS-CoV-2 infection, the pursuit of two major questions is imperative: (1) what is the contribution of T cells to initial virus control and tissue damage in the context of COVID-19, and (2) how do memory T cells established thereafter contribute to protective immunity upon reinfection? Some tentative answers are beginning to emerge.\n\nOverall Reduction of CD4 and CD8 T Cell Counts in Peripheral Blood\nSimilar to earlier observations about SARS-CoV-1 infection (He et al., 2005), several current reports emphasize the occurrence of lymphopenia with drastically reduced numbers of both CD4 and CD8 T cells in moderate and severe COVID-19 cases (Figure 3 ) (Chen et al., 2020c, Nie et al., 2020b, Wang et al., 2020d, Zeng et al., 2020, Zheng et al., 2020b). The extent of lymphopenia—most striking for CD8 T cells in patients admitted to the intensive care unit (ICU)—seemingly correlates with COVID-19-associated disease severity and mortality (Chen et al., 2020c, Diao et al., 2020, Liu et al., 2020b, Liu et al., 2020c, Tan et al., 2020a, Wang et al., 2020d, Wang et al., 2020f, Zeng et al., 2020, Zhou et al., 2020c). Patients with mild symptoms, however, typically present with normal or slightly higher T cell counts (Liu et al., 2020a, Thevarajan et al., 2020). The cause of peripheral T cell loss in moderate to severe COVID-19, though a phenomenon also observed in other viral infections, remains elusive, and direct viral infection of T cells, in contrast to MERS-CoV (Chu et al., 2016), has not been reported.\nFigure 3 Working Model for T Cell Responses to SARS-CoV-2: Changes in Peripheral Blood T Cell Frequencies and Phenotype\nA decrease in peripheral blood T cells associated with disease severity and inflammation is now well documented in COVID-19. Several studies report increased numbers of activated CD4 and CD8 T cells, which display a trend toward an exhausted phenotype in persistent COVID-19, based on continuous and upregulated expression of inhibitory markers as well as potential reduced polyfunctionality and cytotoxicity. In severe disease, production of specific inflammatory cytokines by CD4 T cells has also been reported. This working model needs to be confirmed and expanded on in future studies to assess virus-specific T cell responses both in peripheral blood and in tissues. In addition, larger and more defined patient cohorts with longitudinal data are required to define the relationship between disease severity and T cell phenotype.\nIL, interleukin; IFN, interferon; TNF, tumor necrosis factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GzmA/B, granzyme A/granzyme B; Prf1, perforin.\nSeveral mechanisms likely contribute to the reduced number of T cells in the blood, including effects from the inflammatory cytokine milieu. Indeed, lymphopenia seems to correlate with serum IL-6, IL-10, and TNF-α (Diao et al., 2020, Wan et al., 2020a), while convalescent patients were found to have restored bulk T cell frequencies paired with overall lower proinflammatory cytokine levels (Chen et al., 2020f, Diao et al., 2020, Liu et al., 2020a, Liu et al., 2020b, Zheng et al., 2020b). Cytokines such as IFN-I and TNF-α may inhibit T cell recirculation in blood by promoting retention in lymphoid organs and attachment to endothelium (Kamphuis et al., 2006, Shiow et al., 2006). However, in an autopsy study examining the spleens and hilar lymph nodes of six patients who succumbed to COVID-19, Chen et al. observed extensive cell death of lymphocytes and suggested potential roles for IL-6 as well as Fas-FasL interactions (Chen et al., 2020h). In support of this hypothesis, the IL-6 receptor antagonist tocilizumab was found to increase the number of circulating lymphocytes (Giamarellos-Bourboulis et al., 2020). T cell recruitment to sites of infection may also reduce their presence in the peripheral blood compartment. scRNA-seq analysis of bronchoalveolar lavage (BAL) fluid of COVID-19 patients revealed an increase in CD8 T cell infiltrate with clonal expansion (Liao et al., 2020). Likewise, post-mortem examination of a patient who succumbed to ARDS following SARS-CoV-2 infection showed extensive lymphocyte infiltration in the lungs (Xu et al., 2020c). However, another study that examined post-mortem biopsies from four COVID-19 patients only found neutrophilic infiltration (Tian et al., 2020a). Further studies are therefore needed to better determine the cause and impact of the commonly observed lymphopenia in COVID-19 patients.\n\nInduction of Antiviral T Cell Responses\nAvailable information about SARS-CoV-1-specific T cell immunity may serve as an orientation for further understanding of SARS-CoV-2 infection. Immunogenic T cell epitopes are distributed across several SARS-CoV-1 proteins (S, N, and M, as well as ORF3), although CD4 T cell responses were more restricted to the S protein (Li et al., 2008). In SARS-CoV-1 survivors, the magnitude and frequency of specific CD8 memory T cells exceeded that of CD4 memory T cells, and virus-specific T cells persisted for at least 6–11 years, suggesting that T cells may confer long-term immunity (Ng et al., 2016, Tang et al., 2011). Limited data from viremic SARS patients further indicated that virus-specific CD4 T cell populations might be associated with a more severe disease course, since lethal outcomes correlated with elevated Th2 cell (IL-4, IL-5, IL-10) serum cytokines (Li et al., 2008). However, the quality of CD4 T cell responses needs to be further characterized to understand associations with disease severity. Few studies have thus far characterized specific T cell immunity in SARS-CoV-2 infection. In 12 patients recovering from mild COVID-19, robust T cell responses specific for viral N, M, and S proteins were detected by IFN-γ ELISPOT, weakly correlated with neutralizing antibody concentrations (similar to convalescent SARS-CoV-1 patients; Li et al., 2008), and subsequently contracted with only N-specific T cells detectable in about one-third of the cases post recovery (Ni et al., 2020). In a second study, PBMCs from COVID-19 patients with moderate to severe ARDS were analyzed by flow cytometry approximately 2 weeks after ICU admission (Weiskopf et al., 2020). Both virus-specific CD4 and CD8 T cells were detected in all patients at average frequencies of 1.4% and 1.3%, respectively, and very limited phenotyping according to CD45RA and CCR7 expression status characterized these cells predominantly as either CD4 Tcm (central memory) or CD8 Tem (effector memory) and Temra (effector memory RA) cells. This study is notable for the use of large complementary peptide pools comprising 1,095 SARS-Cov-2 epitopes (overlapping 15-mers for S protein as well as computationally predicted HLA-I- and -II-restricted epitopes for all other viral proteins) as antigen-specific stimuli that revealed a preferential specificity of both CD4 and CD8 T cells for S protein epitopes, with the former population modestly increasing over ∼10–30 days after initial onset of symptoms. A caveat, however, pertains to the identification of specific T cells by induced CD69 and CD137 co-expression, since upregulation of CD137 by CD4 T cells, in contrast to CD154, may preferentially capture regulatory T cells (Treg) (Bacher et al., 2016). Further analyses of S protein-specific T cells by ELISA demonstrated robust induction of IFN-γ, TNF-α, and IL-2 concomitant with lower levels of IL-5, IL-13, IL-9, IL-10, and IL-22. A third report focused on S-specific CD4 T cell responses in 18 patients with mild, severe, or critical COVID-19 using overlapping peptide pools and induced CD154 and CD137 co-expression as a readout for antiviral CD4 T cells. Such cells were present in 83% of cases and presented with enhanced CD38, HLA-DR, and Ki-67 expression indicative of recent in vivo activation (Braun et al., 2020). Of note, the authors also detected low frequencies of S-reactive CD4 T cells in 34% of SARS-CoV-2 seronegative healthy control donors. However, these CD4 T cells lacked phenotypic markers of activation and were specific for C-terminal S protein epitopes that are highly similar to endemic human CoVs, suggesting that crossreactive CD4 memory T cells in some populations (e.g., children and younger patients that experience a higher incidence of hCoV infections) may be recruited into an amplified primary SARS-CoV-2-specific response (Braun et al., 2020). Similarly, endemic CoV-specific CD4 T cells were previously shown to recognize SARS-CoV1 determinants (Gioia et al., 2005). How previous infections with endemic CoV may affect immune responses to SARS-CoV-2 will need to be further investigated.\nFinally, in general accordance with the above findings on the induction of SARS-CoV-2-specific T cells, using TCR sequencing (TCR-seq), Huang et al. and Liao et al. reported greater TCR clonality of peripheral blood (Huang et al., 2020c) as well as BAL T cells (Liao et al., 2020) in patients with mild versus severe COVID-19. Moving forward, a comprehensive identification of immunogenic SARS-CoV-2 epitopes recognized by T cells (Campbell et al., 2020), as well as further studies on convalescent patients who recovered from mild and severe disease, will be particularly important.\n\nT Cell Contribution to COVID-19 Hyperinflammation\nWhile the induction of robust T cell immunity is likely essential for efficient virus control, dysregulated T cell responses may cause immunopathology and contribute to disease severity in COVID-19 patients (Figure 3). This is suggested in a study by Zhou et al., which reported a significantly increased PBMC frequency of polyclonal GM-CSF+ CD4 T cells capable of prodigious ex vivo IL-6 and IFN-γ production only in critically ill COVID-19 patients (Zhou et al., 2020c). Of note, GM-CSF+ CD4 T cells have been previously implicated in inflammatory autoimmune diseases, such as multiple sclerosis or juvenile rheumatoid arthritis, and high levels of circulating GM-CSF+ CD4 T cells were found to be associated with poor outcomes in sepsis (Huang et al., 2019). Additionally, two studies observed reduced frequencies of Treg cells in severe COVID-19 cases (Chen et al., 2020c, Qin et al., 2020). Since Treg cells have been shown to help resolve ARDS inflammation in mouse models (Walter et al., 2018), a loss of Tregs might facilitate the development of COVID-19 lung immunopathology. Similarly, a reduction of γδ-T cells, a subset of T cells with apparent protective antiviral function in influenza pneumonia (Dong et al., 2018, Zheng et al., 2013), has been reported in severely sick COVID-19 patients (Guo et al., 2020, Lei et al., 2020b).\n\nPhenotype and Function of T Cell Subsets in COVID-19\nCurrently, little is known about specific phenotypical and/or functional T cell changes associated with COVID-19. In the majority of preprints and peer-reviewed studies, there are reports of increased presence of activated T cells (Figure 3) characterized by expression of HLA-DR, CD38, CD69, CD25, CD44, and Ki-67 (Braun et al., 2020, Ni et al., 2020, Guo et al., 2020, Liao et al., 2020, Thevarajan et al., 2020, Yang et al., 2020a, Zheng et al., 2020a). Generally, independent of COVID-19 disease severity, CD8 T cells seem to be more activated than CD4 T cells (Qin et al., 2020, Thevarajan et al., 2020, Yang et al., 2020a), a finding that echoes stronger CD8 than CD4 T cell responses during SARS-CoV-1 (Li et al., 2008). Furthermore, in a case study of 10 COVID-19 patients, Diao et al. showed that levels of PD-1 increased from prodromal to symptomatic stages of the disease (Diao et al., 2020). PD-1 expression is commonly associated with T cell exhaustion, but it is important to emphasize that PD-1 is primarily induced by TCR signaling; it is thus also expressed by activated effector T cells (Ahn et al., 2018).\nIn addition, several studies reported higher expression of various co-stimulatory and inhibitory molecules such as OX-40 and CD137 (Zhou et al., 2020c), CTLA-4 and TIGIT (Zheng et al., 2020a), and NKG2a (Zheng et al., 2020b). Reduced numbers of CD28+ CD8 T cells (Qin et al., 2020) as well as larger frequencies of PD-1+ TIM3+ CD8 T cells in ICU patients were also reported (Zhou et al., 2020c). Expression of most of these markers was found to be higher in CD8 than in CD4 T cells, and levels tended to increase in severe versus non-severe cases, which may be due to differences in viral load. Cellular functionality was shown to be impaired in CD4 and CD8 T cells of critically ill patients, with reduced frequencies of polyfunctional T cells (producing more than one cytokine) as well as generally lower IFN-γ and TNF-α production following restimulation with phorbol myristate acetate (PMA) and ionomycin (Chen et al., 2020c, Zheng et al., 2020a, Zheng et al., 2020b). Similarly, Zheng et al. reported that CD8 T cells in severe COVID-19 appear less cytotoxic and effector-like with reduced CD107a degranulation and granzyme B (GzmB) production (Zheng et al., 2020b). In contrast, a different study found that both GzmB and perforin were increased in CD8 T cells of severely sick patients (Zheng et al., 2020a). In accordance with the latter observation, when compared to a moderate disease group, convalescent patients with resolved severe SARS-CoV-1 infection had significantly higher frequencies of polyfunctional T cells, with CD4 T cells producing more IFN-γ, TNF-α, and IL-2 and CD8 T cells producing more IFN-γ, TNF-α, and CD107a, respectively (Li et al., 2008). However, given the vigorous dynamics of acute T cell responses and potential differences in sample timing throughout disease course, these observations are not necessarily mutually exclusive. Accordingly, RNA sequencing (RNA-seq) data by Liao et al. showed that CD8 T cells in the BAL fluid of severe COVID-19 patients express cytotoxic genes such as GZMA, GZMB, and GZMK at higher levels, while KLRC1 and XCL1 are enriched in mild cases (Liao et al., 2020).\nIn summary, T cells in severe COVID-19 seem to be more activated and may exhibit a trend toward exhaustion based on continuous expression of inhibitory markers such as PD-1 and TIM-3 as well as overall reduced polyfunctionality and cytotoxicity. Conversely, recovering patients were shown to have an increase in follicular helper CD4 T cells (TFH) as well as decreasing levels of inhibitory markers along with enhanced levels of effector molecules such as Gzm A, GzmB, and perforin (Thevarajan et al., 2020, Yang et al., 2020a, Zheng et al., 2020b). Collectively, these studies provide a first glimpse into T cell dynamics in acute SARS-CoV-2 infection, but any conclusions have to be tempered at this stage on account of significant limitations in many of the current investigations."}

LitCovid-PD-GO-BP

LitCovid-PubTator

LitCovid-sentences

PMC:7200337 / 28809-43902 JSONTXT

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PMC:7200337 / 28809-43902 JSON TXT