Graduate student University of Toronto, United States
Disclosure(s):
Melissa Yi Ran Liu: No financial relationships to disclose
Introduction/Rationale: 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.
