Transcriptional and metabolic regulation of vaccine-elicited CD8+ T cell responses

PROJECT SUMMARY Due to the overwhelming success of the new mRNA vaccines during the SARS-CoV2 pandemic, vaccines have entered the public consciousness to a level not seen since the days of smallpox eradication and the polio epidemic. It seems reasonable to assume that the established rules governing T cell responses to infections might be useful in developing better subunit vaccine formulations. However, there is mounting evidence that the immunological mechanisms relevant to adjuvant-elicited cellular immunity are vastly different than those observed in response to infectious challenge. Over the last 20 years, we have published extensively on a growing list of factors that highlight the mechanistic distinctions between vaccine-elicited (Tvacs) and infection-elicited (Tinf) T cell responses in mice and non-human primates. Our most recent data has revealed additional features mechanistically unique to Tvacs. Whereas Tinf split their functions between 2 different cell types and either divide or become memory, Tvacs do both within the same cell. Our data support an entirely novel model of CD8+ T cell activation whereby two transcription factors normally opposed to one another in function instead cooperate to sustain Tvacs exponential clonal expansion as well as a memory cell fate. The goals of this project will be to understand how these transcription factors cooperate instead of competing to support a vaccine-elicited T cell's transcriptional and metabolic needs.