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.