CD4+ memory T cells
CD4+ memory T cells are associated with the severity of SARS-CoV-2 infection. Individuals with severe COVID-19 showed higher frequency of CD4+ TEM, while lower frequency of CD4+ TCM compared with patients with mild and moderate symptoms [40, 41]. Meanwhile, the immune response-activating cell surface receptor signaling pathway was significantly upregulated in CD4+ memory T cells of moderate patients and significantly downregulated in the counterpart of severe patients. Besides, the expression of Ly-1 antibody reactive clone (LYAR) , which was related to cell differentiation, was raised in CD4+ memory T cells of COVID-19 convalescent patients (Figure 1). The relative percentage of CD4+ memory cluster was increased significantly in convalescent moderate COVID-19 patients compared with healthy donors and decreased significantly in convalescent severe COVID-19 patients compared with moderate patients [33]. Older convalescent COVID-19 patients had higher expression of activation/proliferation markers (GZMA and GZMK, NFKBIA, DUSP1 ) on the surface of CD4+ memory T cells [42] (Figure 1). Clearly, CD4+ memory T cells can be established in moderate but not in severe patients, while the increased levels of effector molecules on CD4+ memory T cells might contribute to anti-viral responses.
Notably, 20~80% of SARS-CoV-2 unexposed individuals have cross-reactive memory CD4+T cells [43-45]. The cell populations, including CD4 TCM, TEM, tissue-resident memory T cells (TRM) and memory TFH cells, may provide protective immunity against SARS-CoV-2 infection and reduce disease severity by promoting B cell-mediated antibody responses and mediating local antiviral immunity [46] (Figure 1). However, another study showed that pre-existing cross reactive memory T cells had low TCR activity with reduced clonal expansion, exacerbated inflammation and disease severity [47]. Meanwhile, pre-existing CD4+ memory T cells is heterogeneous among individuals due to variable HLA and pre-infection history, which might be associated with different clinical manifestations [47].