PMC:7546716 / 14428-17732
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7546716","sourcedb":"PMC","sourceid":"7546716","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7546716","text":"Cellular expansion in severe–critical COVID-19\nFailure of lymphocytes to adequately respond to viral antigens and proapoptotic signals might induce dendritic cells to produce large amounts of the lymphocyte growth factors IL-7 and IL-2, thereby stimulating T-cell survival and expansion. High concentrations of IL-2 and IL-7 in serum are characteristic of severe COVID-19 cases.6, 9 However, IL-2 and IL-7 might amplify ILC2 survival and differentiation induced by IL-33,33 expand γδ T cells, which produce IL-17 through the signal transducer and activator of transcription (STAT)3,34 and enhance IL-33-induced pathologic expansion of T cells expressing GM-CSF through STAT5.35, 36 Patients infected with SARS-CoV-2 show an increase in circulating CD4+ γδ T cells that overexpress the IL-2 receptor CD25 but not PD-1, suggesting that these cells are not exhausted, but are specifically activated in response to IL-2.22\nIL-7 enables γδ T cells to fully differentiate into γδT17 cells34 that coproduce IL-17F along with IL-17A, and rapidly migrate into inflamed tissues in response to CCR2 and CCR5 ligands such as CCL2 and CCL8.37, 38 As shown for murine γδT17 cells, human Vδ2+ T cells that co-express CCR2 and CCR5 also express the IL-7 receptor and show a Th17-like phenotype (CCR6+CD161+IL-23R+).39 Transcriptional analyses of respiratory cell populations in response to SARS-CoV-2 infection reveal strong upregulation of CCL8, CCL2, CXCL9, CXCL10 and their respective receptors,11, 15, 27 and global upregulation of IL-17 and IL-17F-related pathways,26 including the CCR6 ligand CCL20 and IL-23.27\nIL-23 and IL-1β are required for GM-CSF production by γδT17 cells and conventional αβ Th17 cells.40, 41 In models of autoimmunity in which GM-CSF is a key pathogenic molecule, such as experimental autoimmune encephalomyelitis, γδ T cells have been identified as the major source of GM-CSF.42 Whereas conventional αβ Th17 cells evolve to produce IFNγ during the development of the disease, γδT17 cells are less likely to produce IFNγ and will more likely evolve to produce GM-CSF.42 As for γδT17, recruitment of IL-23-driven, GM-CSF-producing Th17 cells requires CCR2.43\nBy promptly releasing multiple cytokines such as IL-9, IL-17, IL-17F, TNF, IFNγ, and GM-CSF, γδT17 might be instrumental in recruiting neutrophils and proinflammatory monocytes into the capillaries and alveoli of patients with COVID-19. Moreover, activation of γδ T cells might be important in the cytokine-driven induction of procoagulant tissue factor in endothelial cells,44 thus also having a potential role in vascular manifestations and pulmonary thromboses associated with COVID-19 pneumonia.2, 29\nCytotoxicity against virus-infected alveolar epithelial cells by γδ T cells has been shown for influenza virus45 and might involve atypical pathways alternative to granzyme B and perforin, which are more commonly used by CD8+ T cells and natural killer cells and could be impaired in COVID-19 and MAS.1, 29, 31 Specifically, γδ T cells might exert cytotoxic effects through the TNF-related apoptosis-inducing ligand, Fas ligand, and granzyme K,39, 45 which are all overexpressed in the lungs of patients with COVID-19,11, 15 and might therefore explain how γδ T cells cause diffuse damage to the alveolar epithelium (figure 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