Interleukin-10 Directly Inhibits CD8+ T Cell Function by Enhancing N-Glycan Branching to Decrease Antigen Sensitivity

Abstract

Chronic viral infections remain a global health concern. The early events that facilitate viral persistence have been linked to the activity of the immunoregulatory cytokine IL-10. However, the mechanisms by which IL-10 facilitates the establishment of chronic infection are not fully understood. Herein, we demonstrated that the antigen sensitivity of CD8 T cells was decreased during chronic infection and that this was directly mediated by IL-10. Mechanistically, we showed that IL-10 induced the expression of Mgat5, a glycosyltransferase that enhances N-glycan branching on surface glycoproteins. Increased N-glycan branching on CD8 T cells promoted the formation of a galectin 3-mediated membrane lattice, which restricted the interaction of key glycoproteins, ultimately increasing the antigenic threshold required for T cell activation. Our study identified a regulatory loop in which IL-10 directly restricts CD8 T cell activation and function through modification of cell surface glycosylation allowing the establishment of chronic infection.

TIGIT limits immune pathology during viral infections

“…In the context of influenza infection, however, the role of IL-10 still remains controversial as the genetic background appears to have a dominant effect on disease susceptibility 59,60 . More recently, Smith et al demonstrated that IL-10 can act directly on CD8 + T cells by increasing the antigenic threshold for T cell activation and that this process was highly dependent on the dose and timing of exposure 17 . Since the impact of IL-10 is clearly determined by the timing and site of its production, TIGIT modulation might be used as a surrogate to generate a local immune suppressive environment at sites of tissue inflammation.…”

“…Importantly, loss of TIGIT results in hyperproliferative and inflammatory T cell responses and a marked reduction in IL-10 9,14 . IL-10 itself is a key regulator of immune responses during infections, where it plays a two-sided role by both promoting pathogen persistence [17][18][19] as well as limiting excessive Th1 and CD8 + T cell responses that cause immune pathology 20,21 . Incidentally, many chronic or latent human viruses have evolved to encode IL-10 homologs in order to evade immune control 22 .…”

IL-10 and ICOS differentially regulate T cell responses in the brain during chronicToxoplasma gondiiinfection

“…Though the overall number of CD8+ effector T cells in the brain is not increased, we still observed an increased frequency of Ki67+ CD8+ T cells in the brain after IL-10R blockade, suggesting that this population is still responsive to IL-10-mediated suppression; perhaps through an intrinsic response to IL-10 that limits their proliferative capacity. IL-10 has been shown to be able to directly inhibit proliferation of CD8+ T cells in vitro [14], as well as control the threshold of their response to antigen upon initial activation [68]. Much is still unknown about the direct effects of IL-10 on activated CD8+ T cells that could contribute to their regulation, though these data further suggest that CD8+ effector T cells may be differentially regulated from the CD4+ effector T cell compartment in the brain.…”

Gastric cancer patients display a distinctive population of IFNg+IL10+ double positive CD8 T cells, which persists longer during prolonged activation

“…IL10 is shown to suppress innate and adaptive immune responses, mediate tissue repair, and maintain epithelium integrity [17]. In addition, IL10 can directly dampen the signal transduction of CD8 T cells, thus increasing the threshold required for antigen recognition and activation [18]. Interestingly, polymorphisms that increase IL10 production are associated with elevated GC risk [19][20][21], which is contrary to the hypothesis that IL10 may prevent inflammation-induced disruption of the epithelium.…”