Characterizing the roles of the PD-1 ligands, PD-L1 and PD-L2, in regulating the T cell response to influenza virus

During normal flu seasons, Influenza virus is estimated to cause an average of 250,000-500,000 deaths. Vaccination against Influenza poses challenges due to the high mutation rates of the virus; Influenza A virus vaccines rarely protect for more than a few years. One limiting factor in the success of our current vaccination strategy is the failure to induce long-lasting CD8 T cell memory.;In this dissertation I have utilized a heterotypic Influenza A infection model, in concert with PD-1 ligand-deficient mice (PD-L1/L2-/- and 3 different flu-specific CD8 T cell tetramers in order to investigate the roles of PD-L1 and PD-L2 in regulating the primary and secondary CD8 T cell response to influenza virus. My studies show that PD-L1/L2-/- mice exhibit a significant increase in virus-specific T cell numbers at the peak of the primary immune response, concomitant with accelerated viral clearance, as compared to wild type mice. This enhanced effector response in PD-L1/L2-/- mice is followed by a delay in the contraction phase, and subsequent reductions in subdominant virus-specific CD8 T cells at memory timepoints. Secondary challenge with influenza virus demonstrated functional consequences of reduced flu-specific CD8 T cells after primary infection. Following secondary infection PD-L1/L2-/- mice lost significantly more weight, experienced delayed flu-specific CD8 T cell expansion and effector function within the lungs, exhibited more intense inflammation within the lungs, and demonstrated a substantial delay in viral clearance, as compared to wild type mice.;Taken together, my studies have revealed important roles for PD-L1 and PD-L2 during the primary response to viral infection, where they function to dampen the CD8 T cell response, and also in the generation/maintenance of memory CD8 T cells. PD-L1/L2-/- mice exhibited enhanced influenza-specific effector CD8 T cell responses but impaired influenza-specific memory CD8 T cell responses. These findings challenge one of the paradigms about the immune response to a pathogen: the greater the effector response, the more memory cells are generated. My work suggests a new approach for enhancing CD8 T cell memory: administration of PD-1 agonists during vaccination may provide a means to induce long lasting CD8 T cell memory responses.