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.