NKT cells
NKT cells are the special T cell population expressing semi-invariant αβTCR, which recognize glycolipid antigens presented by the HMC-I-like molecule CD1d, and a number of surface antigens in common with natural killer cells. The features that NKT cells not only recognize antigens but also immediately secrete effector cytokines encountering pathogens, which endow them with the ability in defensing against virus infection via innate immunity and adaptive immunity [74]. ScRNA-seq analysis defined three subsets of NKT cell clusters, including naive NKT cells (CCR7+SELL+), CD56+ NKT cells and CD160+ NKT cells in patients with COVID-19 (Figure 1). Among them, the CD160+ NKT cells refer to a previously described γδ NKT or Vδ1 T cells, which showed phenotypical and functional similarity to traditional NK cells [28]. The proportion of naive NKT cells decreased, while CD56+ NKT, CD160+NKT and pro-NKT (LAMP1+CD4+CD8+) cells increased in COVID-19 patients. And the abundance of CD160+ NKT cells was significantly reduced in severe patients compared to moderate patients [22, 28], while intensively expanded in convalescent patients with moderate COVID-19 [33]. Furthermore, the pregnant patients who had more NKT cells than the non-pregnant groups, expressed high chemotaxis, which might contribute to the control of SARS-CoV-2 infection [75]. Moreover, Yang et al found that the increased expression of Tim-3 promoted depletion of NKT cells and associated with the disease severity. Tim-3+NKT cells expressed high levels of apoptosis, mitochondrial genes and caspase genes, and secreted high level of IFN-g, IL-4 and IL-10 compared to healthy individuals [74] (Figure 1). Hence, a new strategy by regulating Tim-3 signal pathway in NKT cells might be helpful for elimination of lethal epidemic caused by SARS-CoV-2 infection [74].
Upon SARS-CoV-2 infection, NKT cells expressed multiple effector molecules to promote rapid resolution of infection through their direct cytotoxicity. For example, CD56+ NKT and CD160+ NKT cells expressed high levels of NKG7, GZMA, GZMB, GZMH and GNLY [28] (Figure 1). Moreover,FCGR3A was enriched in CD160+ NKT cells, which may mediate the antibody-dependent cell-mediated cytotoxicity [28] (Figure 1). CD8B and TRDC were upregulated in NKT cells in severe convalescent patients, which provided evidence for direct antiviral role [33, 76]. On the other hand, NKT also play pathogenic roles in the pathogenesis of COVID-19. Activated NKT cells together with other innate immune cells secrete additional cytokines to target virus-infected cells, and their overstimulation may lead to tissue damage [77]. Similarly, LAG3+CD160+CD8+NKT cells increased significantly in the symptomatic patients compared with the asymptomatic individuals [22]. The differentially expressed genes in the LAG3+CD160+CD8+NKT, for example IFNG, CXCR4, LGALS1 and XCL2, were linked to immune responses, inflammation and apoptosis [22]. Thus, these characteristics contribute to the responses to SARS-CoV-2 infection, and also play pathogenic roles in the pathogenesis of COVID-19.