Tim-3 deletion on Treg increases virus-specific T cell response and reduces viral burden in 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. Similarly, it’s been recently reported that there is an increase in Tim-3+ Treg in people with HIV (PWH). 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 blood, liver, and kidney at 30dpi. Lack of Tim-3 expression on Treg limited their ability to upregulate IL-10, TGFb, CD39, PD-1, CD25, CTLA-4 and CD44. Similarly, in PWH Tim-3+ Treg have increased expression of IL-10 compared to HIV(−). In addition, Tim-3+ Treg from PWH show significant upregulation of Ki67+, CD73+, Gzmb+ and TGFb+ compared to their Tim-3− Treg counterpart. Our findings demonstrate that modulation of a surface protein in Treg can lead to a reduction in viral burden and enhance LCMV-specific T cell response. We found that Tim-3+ Treg have an increased suppressive phenotype, compared with Tim-3− Treg in PWH, regardless of viral suppression. Elucidation of the mechanism of Tim-3 function in Treg may provide insights into the biology of chronic infections and for developing novel potential strategies to achieve HIV remission off ART. Supported by grants from NIH (T32GM008208, R01AI138504, U01AI131285)