CD8+ effector T cells
CD8+ effector T cells are the key population for defending against viral infection through eliminating virus and virus-infected cells. The proportion of CD8+ effector T cells was higher in COVID-19 patients compared to the healthy group, but lower in severe compared with non-severe group [23]. However, another study performed by scRNA-seq analysis revealed that the number of CD8+ effector T cells were increased in severe and critical COVID-19 patients compared to healthy donors, which might be associated with the low expression of ZBTB7B and high expression of CBFB, EP300 and RUNX3 [24]. Meanwhile, the dysfunction of CD8+ effector cells in severe and critical COVID-19 patients manifested themselves in the high expression of apoptosis-related genes (MAF ) and exhaustion-related genes, and the attenuated function of proliferation [24]. The genes enriched in “IL-17 signaling pathway” and “response to toxic substance” expressed in the CD8+ effector T cells of COVID-19 patients were down-regulated [24]. In contrast, activated CD8+ T cells exhibited higher levels of cytotoxicity molecules, such as GZMB and perforin in severe COVID-19 patients than in the mild COVID-19 patients [62] (Figure 1). In addition, the abundance of effector CD8+ T cells were diversity across age groups. Older patients tend to have a high proportion of effector CD8+T cells relative to younger counterparts [42].
Similar to CD4+ effector T cells, CD8+ effector-GZMK and CD8+effector-GNLY T cells were also found in COVID-19 patients. CD8+ effector-GZMK cells uniquely expressingGZMK , showed highly exhausted status and high proportion of clonal cells, whereas CD8+ effector-GNLY cells expressing high level of GZMB/H and GNLY , showed high proportion of activate state and clonal expansion, and enhanced cytotoxicity [28, 33] (Figure 1). In bronchoalveolar lavage samples, highly clonally expanded CD8+ T cells expressed higher levels of GZMK, GZMA and FASLG and the tissue-residence markers ITGA1, CXCR6 and JAML . This population had upregulation of genes involved in activation, migration and cytokine-related pathways in moderate cases and cell homeostasis, translation initiation and nucleoside metabolic pathways in severe cases [60]. In child patients, there were greater IFN, inflammasome signaling, widespread T cell activation [63] and a subpopulation of KLRC1 (NKG2A+) cytotoxic T cells (CTL2) predominantly [64]. NKG2A is a lectin-like inhibitory receptor on cytotoxic T cells and plays a role in limiting excessive activation, preventing apoptosis and sustaining the virus-specific CD8+ T cell response [64] (Figure 1). However, persisting stimulation of CD8+ T-cells resulted in exhaustion. Therefore, simultaneous consideration of improving virus-specific CD8+ T cells activation, proliferation, cytotoxic capacity and limiting exhaustion is needed for COVID-19 immunotherapy.