Abstract
In the ongoing coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), natural killer T (NKT) cells act as primary initiators of immune responses. However, a decrease of circulating NKT cells has been observed in COVID-19 different stages, of which the underlying mechanism remains to be elucidated. Here, by performing single-cell RNA sequencing analysis in three large cohorts of COVID-19 patients, we found that increased expression of Tim-3 promotes depletion of NKT cells during the progression stage of COVID-19, which is associated with disease severity and outcome of patients with COVID-19. Tim-3+ NKT cells also expressed high levels of CD147 and CD26, which are potential SARS-CoV-2 spike binding receptors. In the study, Tim-3+ NKT cells showed high enrichment of apoptosis, higher expression levels of mitochondrial genes and caspase genes, with a larger pseudo time value. In addition, Tim-3+ NKT cells in COVID-19 presented a stronger capacity to secrete IFN-γ, IL-4 and IL-10 compared with healthy individuals, they also demonstrated high expression of co-inhibitory receptors such as PD-1, CTLA-4, and LAG-3. Moreover, we found that IL-12 secreted by dendritic cells (DCs) was positively correlated with up-regulated expression of Tim-3 in NKT cells in COVID-19 patients. Overall, this study describes a novel mechanism by which up-regulated Tim-3 expression induced the depletion and dysfunction of NKT cells in COVID-19 patients. These findings not only have possible implications for the prediction of severity and prognosis in COVID-19 but also provide a link between NKT cells and future new therapeutic strategies in SARS-CoV-2 infection.
Highlights
Coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a serious threat to public health [1]
The findings indicated that the number of circulating Natural killer T (NKT) cells in COVID-19 patients decreased while Tim-3+NKT cells increased, and the expression of Tim-3 was associated with the outcomes of COVID-19 patients
Consistent with previous studies, we found that the percentage of CD8+T cells, mucosalassociated invariant T (MAIT) cells, gd T cells, mono-dendritic cells (DCs), and plasmacytoid dendritic cells (pDCs) decreased significantly as the disease progressed, while the percentage of plasma B cells, CD14+ monocytes, and platelets increased significantly, there was no significant change in the number of NK cells (Figure S1) [25, 27, 35].Of note, the percentage of NKT cells in severe COVID-19 patients decreased significantly in both progression and convalescence (Figure 1F), which is consistent with previous studies [13, 14]
Summary
Coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a serious threat to public health [1]. NKT cells exert their antiviral functions by directly lysing target cells, recruiting, stimulating, and regulating other innate cells such as NK cells and neutrophils [9]. NKT cells regulate adaptive cells by promoting B cells to proliferate and produce antibodies, as well as the responses of T cells against intracellular viruses [9]. Recent studies showed that the number of circulating NKT cells in the peripheral blood of patients with COVID-19 decreased [1, 12– 15]. NKT cells showed the ability to enhance vaccinemediated immune response [16], which may be explained by the fact that NKT cells play distinct roles in different stages of COVID-19. The underlying mechanism of NKT cells depletion and the activity regulation during SARS-CoV-2 infection remain to be further elucidated
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