CD4-CTLs
CD4-CTLs are recently defined as terminal effector T cell population to secrete GZMB and perforin and serve as an important component of antiviral and antitumor immunity [11]. A study from Meckiff et al showed that SARS-CoV-2 reactive CD4+T cells were enriched for CD4-CTLs, which were characterized by high level ofPRF1,GZMB, GZMH, GNLY and NKG7 transcripts [35] (Figure 1). Several molecules like CD72, GPR18, HOPX and ZEB2, are enriched to this population to enhance T cell proliferation, effector differentiation, persistence and survival [35]. Moreover, a number of transcripts encoding for chemokines like CCL3, CCL4 and CCL5 are enriched for CD4-CTLs to recruit innate immune cells, as well as transcripts encoding for XCL1 and XCL2 to promote CD8+ T cells responses by antigen cross presentation of conventional type 1 dendritic cells (cDC1). Thus, CD4-CTLs responses may be linked to pathogenesis. Indeed, CD4-CTLs clusters were present at higher frequencies in some hospitalized COVID-19 patients compared to non-hospitalized patients [36, 37]. In addition, single cell TCR sequence analysis can be used to explore the clonal expansion of T cell subsets. Large clonal expansion of the SARS-CoV-2 virus reactive CD4+ T cells was observed in hospitalized patients compared to non-hospitalized patients (55.8% vs. 38.0%), especially for CD4-CTLs subsets (>75% of cells) [35]. Therefore, CD4-CTLs may directly clear virus like CD8+T cells and also contribute to lung inflammation in severe COVID-19 patients.