Tim-3+ Treg control viral persistence and effector T cell responses.

Tim-3, a surface protein, is upregulated on Treg during chronic viral infections. However, the role of regulatory T cells (Treg) during persistent viral infections 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. First, we used flow cytometry to evaluate the immunosuppressive phenotype and signaling pathways in peripheral Tim-3- versus Tim-3+ Treg in people with HIV on antiretroviral therapy (PWH-ART). Tim-3+ Treg showed an increased expression of IL-10 compared to persons without HIV-1 (PWOH), and elevated phosphorylation signaling relative to Tim-3- Treg in PWH-ART. Tim-3 blockade restrained the in vitro suppressive capacity of peripheral Treg. Therefore, our data demonstrate that Tim-3 contributes directly to the enhanced suppressive activity of Treg in this setting. For the second part of this project, we employed an inducible Treg-specific Tim-3 loss-of-function (Tim-3 Treg KO) murine model to dissect the role of Tim-3 on Treg during LCMV chronic viral infection. We found a significant decrease in morbidity, a more potent virus-specific T cell response, and a significant decrease in viral burden. Tim-3 Treg KO mice exhibited a decrease in the frequency of PD-1+Tim-3+ and PD-1+Tox+ LCMV-specific CD8 T cells. Our findings demonstrate that modulation of a single surface protein in Treg can lead to a reduction in viral burden, limit T cell exhaustion, and enhance LCMV-specific T cell response. These studies may help to identify Tim-3-directed therapies for the management of persistent infections and other chronic illnesses.