No abstract

Resolution of virus infections depends on the priming of virus-specific CD8 T cells by dendritic cells (DC). While this process requires major histocompatibility complex (MHC) class I-restricted antigen presentation by DC, the relative contribution to CD8 T cell priming by infected DC is less clear. We have addressed this question in the context of a peripheral infection with herpes simplex virus 1 (HSV). Assessing the endogenous, polyclonal HSV-specific CD8 T cell response, we found that effective T cell priming depended on the presence of DC subsets specialized in cross-presentation, while Langerhans cells and plasmacytoid DC were dispensable. Utilizing a novel mouse model that allows for the elimination of infected DC, we also demonstrated that this requirement for cross-presenting DC was not related to their infection but instead reflected their capacity to cross-present HSV-derived antigen. Taking the results together, this study shows that infected DC are not required for effective CD8 T cell priming during a peripheral virus infection. The ability of some DC to present viral antigen to CD8 T cells without being infected is thought to enable the host to induce killer T cells even when viruses evade or kill infected DC. However, direct experimental proof for this notion has remained elusive. The work described in this study characterizes the role that different DC play in the induction of virus-specific killer T cell responses and, critically, introduces a novel mouse model that allows for the selective elimination of infected DC Our finding that HSV-specific CD8 T cells can be fully primed in the absence of DC infection shows that cross-presentation by DC is indeed sufficient for effective CD8 T cell priming during a peripheral virus infection.

Interactions with the microbiota influence many aspects of immunity, including immune cell development, differentiation and function. Here we examined the impact of microbiota on one of the key functions of CD8+T cells, the transition to long-lived and protective memory. Antigen-activated CD8+T cells transferred into germ-free mice failed to transition into long-lived memory cells with enhanced recall capacity and had transcriptional impairments in oxidative metabolism. To the contrary, the microbiota-derived short-chain fatty acid (SCFA) butyrate promoted cellular metabolism, enhanced memory potential of activated CD8+T cells and was required for optimal recall responses upon antigen re-encounter. Mechanistic experiments revealed that the SCFA butyrate increased turnover of glycolysis and oxidative phosphorylation (OXPHOS) of effector CD8+T cells but led to a partial uncoupling of the tricarboxylic acid cycle from glycolytic input. This allowed preferential fueling of oxidative phosphorylation through short-chain fatty acids. Our findings reveal a role for the microbiota in promoting CD8+T cell long-term survival as memory cells and suggest that microbial metabolites potentially guide the metabolic rewiring of activated CD8+T cells that enables this transition.