Memory CD8+ T cell-induced activation of the innate immune system drives inflammation and anti-viral immunity 3109

Abstract Description CD8+ T cells play a pivotal role in protective immune responses against intracellular pathogens and tumors. Most CD8+ T cells activated during a primary immune response will contract and die, however, a small percentage persist to form long-lived memory populations (CD8+ Tmem). CD8+ Tmem rapidly deploy their effector functions (i.e., cytotoxicity, cytokine secretion) to respond to subsequent antigen challenges. While these canonical roles are critical, previous studies have suggested that CD8+ T cells can confer protection in the absence of their cytotoxic machinery. The underlying mechanisms for such non-canonical roles remain ill-defined. Our studies have discovered that CD8+ Tmem engage myeloid cells, namely dendritic cells (DCs), in a cognate fashion to drive robust innate inflammatory responses indicative of both NF-kB and IRF activation. These responses appear to be driven by TNFSF ligand-receptor interactions between CD8+ Tmem and DCs, respectively. The ability to induce innate inflammation is directly correlated with the expression of certain TNFSF ligands, and lack of inhibitory molecules, on CD8+ Tmem. These data suggest an evolutionary adaptation wherein CD8+ Tmem facilitate protective responses not only through direct effector functions, but also by inducing broad innate inflammation. Thus, we propose memory CD8+ T cells as surrogate microbes that can initiate proinflammatory and anti-viral responses through previously unexplored mechanisms. Funding Sources Cincinnati Children’s Research Foundation Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)