MAIT cells
MAIT cells, a subset of innate-like T cells, are primarily located in mucosal epithelia defending against microbial activity and infection by recognizing antigens presented by the monomorphic MHC-I related molecule, MR1 [20, 81]. Firstly, the transcriptional profiles of MAIT cells from patients with severe disease were different compared with those from patients with moderate disease, with downregulated canonical markers SLC4A10 and TRAV1-2 and upregulated genes TRBV9, TRAV8-2, S100A8, GZMH, S100A9, KLF6, CD8B, KLRD1, IGLV3-19 and JCHAIN (Figure 1). The differentially expressed genes might correlate with the disease severity [20]. Secondly, the frequency of MAIT-cells in peripheral blood was reduced in a COVID-19 severity-dependent manner [70, 75, 82]. The proportion of naive (CD45RA+CD197+)-like MAIT cells was significantly decreased and the proportion of TEM (CD45RA-CD197-)-like MAIT cells was significantly increased in patients with severe COVID-19 compared to healthy controls (Figure 1) [83]. The cause of the loss of MAIT cells in peripheral blood of severe COVID-19 patients remained unknown. ScRNA-seq analysis revealed that high levels of molecules related to apoptosis and pyroptosis might contribute to the decline of peripheral MAIT cells. In addition, high level of cell chemotaxis expressed on peripheral MAIT cells was observed in patients with severe disease, suggesting the increased migration of MAIT cells to inflammatory tissues. Hence, the pulmonary recruitment may contribute to MAIT cell reduction [20, 83]. Thirdly, despite reduced abundances, MAIT cells showed increased activation in severe and non-severe COVID-19 patients [23]. Notably, the activation levels of MAIT cells in severe cases were less than those in moderate and convalescent cases [20]. The high activation of MAIT cells suggested consistent responses to SARS-CoV-2 infection.
MAIT cells from patients in intensive care unit (ICU) expressed higher levels of genes involved in the inflammatory response (NFKBIA, TXNIP and CD69 ) and decreased levels of IFITM1 [84]. Moreover, the cytotoxic responses genes (GNLY, PRDM1 andPRF1 ) and the key transcription factors (HOBIT andTBX21 ) that induce and maintain cellular production of GZMB were upregulated in ICU patients [84]. Besides, other study found that IFN-stimulated genes, such as IFITM1, IFITM2, and IFITM3,exhibited greater levels in peripheral MAIT cells of COVID-19 patients compared to those from healthy controls. Blocking IFN-α rescued MAIT cell function in patients with severe COVID-19 [84]. MAIT cells in pregnant COVID-19 patients showed higher proinflammatory profile (IFNGR1, STAT1 , TNFRSF1B, TNFAIP3, and TNFSF8 ), and higher chemotaxis signature (CXCR4 ) than the non-pregnant COVID-19 patients [75]. Altered MAIT cell functions may contribute to disease severity through influencing IFN-α–IL-18 imbalance [84]. Herein, MAIT cells serve as a double‐edged sword mediating both protective and pathogenic processes after SARS-CoV-2 infection, and MAIT cell-based therapies worth considering.
T cell based therapeutic options for COVID-19
Several therapeutic approaches, such as antivirals [85-88] and monoclonal antibodies targeting SARS-CoV-2 [85] have been used for COVID-19 treatment. Strategies focused on improving T cell responses and Th1 responses, reversing T-cell exhaustion and settling inflammation are promising approaches for COVID-19 treatments (Figure 2).