Differentiation, programming, and (dys)functions of cytotoxic CD4 T cells in acute and chronic viral infection 2257364

Abstract

Abstract Introduction Killing of virus infected cells 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 for CD4-CTL in controlling infection. Immune activity and effector cell differentiation mediated by antigen presenting cells (APC) can also potentially be modulated by CD4-CTL targeting. We have identified cytotoxic activity as a main CD4 T cell function restored by anti-PD-L1 during chronic LCMV infection. Conversely, the role of CD4-CTL in acute infections is unclear. Methods We used two strains of Lymphocytic choriomeningitis virus (LCMV), Armstrong and Clone 13, to study the role of cytotoxic CD4 in acute and chronic viral infections in mice. Results In acute lymphocytic choriomeningitis virus (LCMV) infection, we demonstrate that CD4-CTL are restricted to the Th1 subset, are associated with the highest level of metabolic and functional activation, and have a distinct transcriptional and epigenetic profile compared to non-CTL Th1 cells. Interestingly, the initial CD4-CTL response forms the basis for maintaining long-term CD4 CTL-reactivatable memory following rechallenge. In vivo, CD4-CTL target B cells via MHC-II in a perforin-dependent manner, and we are exploring a potential role of CD4-CTL to tune B cell immunity and enable a focused immune response. Interestingly, during chronic LCMV infection, alterations in transcriptional programming restrict the induction of CD4-CTL, despite the presence of Th1 cells, underpinning a previously unrecognized quality of CD4 T cell exhaustion. Conclusion Together, my findings provide fundamental insights into the role of CD4-CTL in shaping the antiviral immune response in both acute and chronic infection. Funding Source n/a Topic Categories Viral Immunology (VIR)