Both ILC2 and γδ T cells are centrally involved in lung homoeostasis and are rapidly activated in response to pathogens including viruses;19, 21 in COVID-19, IL-4 is upregulated at early stages and in milder forms of the disease,10 whereas IL-9 and activated γδ T cells are observed more frequently in mild-to-moderate disease,9, 22 and IFNγ and IL-17 progressively increase with disease severity.6 Vγ9Vδ2+ T cells from patients with COVID-19 have been found to express an effector memory phenotype three times more frequently than do conventional αβ T cells,23 thus suggesting that this T cell subset is selectively stimulated in COVID-19. Because of significantly higher expression of the chemokine receptor CXCR3 compared with their αβ counterparts,24 γδ T cells might be rapidly recruited into inflamed lungs of patients with COVID-19 in response to the observed strong upregulation of the CXCR3 ligands CXCL9 and CXCL10 (figure 1 ).6, 9, 11, 15, 25, 26, 27, 28
Figure 1 T-cell polarisation in COVID-19
IL-33 released from virus-damaged cells might induce dysregulated GATA3+Foxp3+ Tregs and promote IL-2 production by dendritic cells, resulting in further expansion of Tregs. IL-33 might also elicit differentiation of ILC2, with TGFβ enhancing ST2 expression on these cells and facilitating production of IL-9. IL-9 in turn stimulates expansion of effector memory Vγ9Vδ2+ T cells with mixed Th1 and Th17 profiles that express CXCR3 and are recruited to the lungs by CXCL9 and CXCL10. IL-9 possibly induces its own transcription factor PU.1 and thus act in an autocrine and paracrine manner (along with TGFβ) to drive proliferation and survival of ILC2 and γδ T cells. Additional positive loops might be fed by IFNγ, which triggers production of CXCL9 and CXCL10 by macrophages. In severe forms of COVID-19, IL-33, along with IL-2 and IL-7 released by dendritic cells, might further stimulate T-cell expansion through STAT5 and induce production of large amounts of GM-CSF by γδ and T helper cells. At advanced stages of disease, aberrant activation of the MyD88-related NF-κB pathway and activation of the NLRP3 inflammasome might induce virus-exposed cells and infiltrating monocytes–macrophages to overproduce IL-1β, IL-23, and IL-6. IL-1β, IL-23, IL-6, and IL-7 act on STAT3 and RORC, thus promoting differentiation of CCR2+ T cells that are recruited to the lungs by CCL2 and CCL8 into γδT17 and Th17 cells producing IL-17 and GM-CSF. In turn, GM-CSF might further recruit and activate proinflammatory monocytes–macrophages. CCR=C-C motif chemokine receptor. CCL=C-C motif chemokine ligand. CXCL=C-X-C motif chemokine ligand. CXCR=C-X-C chemokine receptor. Foxp=forkhead box protein. GATA=GATA-binding factor. GM-CSF=granulocyte-macrophage colony-stimulating factor. IL=interleukin. ILC2=type 2 innate lymphoid cell. MyD88=myeloid differentiation primary response protein. NF-κB=nuclear factor-kappa B. NLRP=NACHT, LRR, and PYD domains-containing protein. PU.1=transcription factor PU.1. RORC=nuclear receptor ROR-gamma. ST2=ST2 receptor. STAT=signal transducer and transcription activator. TGF=transforming growth factor. Th=T-helper. TLR=toll-like receptors. Treg=regulatory T cell.