Tim-3 expression in Treg controls viral persistence and effector T cell response during chronic LCMV infection.

Abstract

Abstract Tim-3, a surface protein, is upregulated on Treg during chronic viral infections. During HCV infection in humans there is an increase in frequency of Tim-3 +Treg, which have increased proliferation, survival, and expression of immunosuppressive cytokines like IL-10, compared to Tim-3 −Treg. Similarly, it was recently reported that there is an increase in Tim-3 +Treg in people with HIV regardless of viral suppression. However, the role of regulatory T cells (Treg) during chronic viral infection has not been fully defined. We hypothesize that Tim-3 promotes an effector phenotype on Treg during chronic viral infection, which limits the virus-specific T cell response and impairs viral clearance. Using an inducible Treg-specific Tim-3 loss-of-function (Tim-3 Treg KO) model, we found a significant decrease in morbidity during LCMV chronic infection. Tim-3 Treg KO mice mounted a higher virus-specific T cell response and had lower viral burden in liver, and kidney at 30 days post-infection. Interestingly, we found that there was a decrease in the frequency of PD-1 +Tim-3 +and PD-1 +Tox +LCMV-specific CD8 T cells. Lack of Tim-3 expression on Treg limited their ability to upregulate IL-10, TGFb, CD39, PD-1, CD25, CTLA-4 and CD44. Our findings demonstrate that modulation of a single surface protein in Treg can lead to a reduction in viral burden and enhance LCMV-specific T cell response. These studies may also help to identify Tim-3 directed therapies for the management of persistent infections and other chronic illnesses. Supported by grants from NIH (T32GM008208, R01 AI138504)