Similar 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.
Figure 3 Working Model for T Cell Responses to SARS-CoV-2: Changes in Peripheral Blood T Cell Frequencies and Phenotype
A 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.
IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GzmA/B, granzyme A/granzyme B; Prf1, perforin.