CD44 controls T cell exhaustion and viral persistence during chronic viral infection (VIR10P.1170)

Abstract

Abstract During a chronic viral infection, inhibitory receptors play a crucial role in controlling viral persistence and T cell exhaustion. However, the role of homing molecules in this process has been poorly investigated. Using the chronic LCMV virus model, Clone 13, we found that expression of CD44, a cell surface glycoprotein broadly used to identify activated T cells, dampens antigen specific T cell responses. In CD44-deficient hosts, we observed a significant increase in antigen specific CD4 and CD8 T cells functions with decreased PD-1 expression and a striking increase in multiple cytokine production. T cell accumulation was not due to increased proliferation based on BrdU incorporation, and the increased CD8 T cell response required CD4 T cell help because CD8 T cell exhaustion was maintained in CD4 depleted CD44-deficient mice. Using a bone marrow chimera approach, we found that restricting the CD44 deficiency in the non-hematopoietic compartment was sufficient to reproduce the observations made in the complete CD44 deficient hosts. Finally CD44-deficiency resulted in viral clearance by d15pi. Importantly, treatment of WT mice with a CD44-blocking antibody increased antigen specific CD4 and CD8 T cell recovery and some aspects of T cell function as early as d9pi. Taken together, these results indicate that CD44 is a novel inhibitory receptor that can be targeted to improve T cell response during chronic viral infections.