TFH cells
TFH cells are specialized providers for priming B cells differentiation and potent antibody responses in germinal center of secondary lymph organs [10]. The circulating TFHcells expressing CXCL13, IL21, CD100, BTLA and POU2AF1 increased in patients with COVID-19 during acute infection, while the frequency of SARS-CoV-2-reactive CD4+ T cells with a TFH profile was not significantly different between hospitalized and non-hospitalized COVID-19 patients [35]. ScRNA-seq further revealed two subsets of circulating TFH cells, cytotoxic TFH cells and non-cytotoxic TFH cells [35]. Cytotoxic TFH cells expressed high levels of transcription factors zinc finger BED-type-containing 2 (ZBED2 ), zinc finger and BTB domain-containing protein 32 (ZBTB32 ) GZMB and PRF1[35] (Figure 1). The relative proportion of cytotoxic TFH cells was significantly greater in hospitalized COVID-19 patients compared to non-hospitalized patients and showed a strong negative correlation with anti S1/S2 antibody levels in hospitalized COVID-19 patients, and the inverse was observed for the proportion of non-cytotoxic TFH cells [35]. Furthermore, cytotoxic TFH cells were reported to kill B cells and hobble the germinal center responses in some children who developed recurrent tonsillitis [38]. Hence, cytotoxic TFH cells might be related with the striking loss of germinal enter B cells in the patients who died of SARS-CoV-2 infection [39]. Taken together, converting cytotoxic TFH cells which killed B cells to non-cytotoxic TFH cells which enhanced antibody responses may be a useful therapeutic strategy for COVID-19 patients. The mechanism of the aberrant GZMB expression by TFH cells after SARS-CoV-2 infection need further study.