Cytotoxic CD4 T cells in acute and chronic viral infection 3631

Abstract Description Immune cell cytotoxicity is associated with CD8 cytotoxic T lymphocytes (CTL) and NK cells; however, CD4 T cells can also exhibit cytotoxic properties. In response to viral infections and cancers, cells downregulate MHC-I but maintain MHC-II, thereby preventing CD8-CTL killing and enabling CD4-CTL targeting. Further, CD8-CTL are functionally exhausted during chronic infections, limiting their ability to kill and providing a potential role of CD4-CTL in controlling chronic infection. In fact, we recently identified CD4-CTL activity as a main CD4 T cell function restored by anti-PD-L1 during chronic LCMV infection. Conversely, although CD4-CTL are generated in acute infections, their role is unclear. In acute murine infections, we demonstrate that CD4-CTL are restricted to the Th1 subset, although not all Th1 are cytotoxic, and are associated with the highest level of metabolic and functional activation. In vivo, we show that these cells target B cells via MHC-II in a perforin-dependent manner, and we are uncovering a potential evolutionary role of CD4-CTL to tune B cell immunity and enable a focused immune response. Interestingly, during chronic LCMV infection, CD4 killing fails to form, despite the presence of Th1 cells, which indicates a molecular mechanism restricting the induction of cytolytic activity. Ultimately, we propose that CD4-CTL have important roles at multiple stages of the acute and chronic immune response to tune the quality of antiviral immunity. Topic Categories Viral Immunology (VIR)