The function and utility of self-specific CD8 T cells

Abstract

Self-specific CD8 T cells have the potential to provide great benefit, but also to cause great harm. This thesis research seeks to uncover the mechanisms controlling CD8 T cell tolerance to self and tumor antigens. We show that the induction of CD8 T cell tolerance is dependent on inhibitory receptor signaling, but the maintenance of tolerance is not. Thus, only newly primed self-specific CD8 T cell are amenable to immune checkpoint blockade activation. We establish CD8 T cell tolerance as an active state of differentiation that is dependent on suppressed antigen-sensing. We demonstrate that robust stimulation with self-antigen and inflammation induces avidity maturation of the self-specific CD8 T cell repertoire, which serves to renew susceptibility to immune checkpoint and aid in anti-tumor responses. We validate that endogenous self-specific CD8 T cells exist within the immune repertoire and can expanded by similar vaccination methods. Expanded self-specific CD8 T cells generate tissue resident memory in non-lymphoid tissues and secondary lymphoid organs, that are phenotypically distinct from non-self-specific populations. Finally, we show that self-specific CD8 T cells synergize with tumor neo-antigen specific CD8 T cells in the treatment and prevention of cancer. This data provides significant insight into the requirements for the induction of self and anti-tumor T cell responses.