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

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SummaryChronic 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.Graphical AbstractHighlightsIL-10 directly increases the threshold for CD8+ T cell activationInduction of Mgat5 is necessary for IL-10-mediated repressionThe galectin-glycoprotein surface lattice promotes T cell dysfunctionDisruption of galectin binding restores T cell function and viral controlThe mechanisms by which IL-10 facilitates the establishment of chronic infections are not fully understood. Smith et al. demonstrate that during chronic infections, IL-10 upregulates N-glycan branching on CD8+ T cell surface glycoproteins, which reduces signal transduction downstream of the T cell receptor and decreases CD8+ T cell antigen sensitivity and capacity to control pathogen burden.

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