Non classical immunity controls microbiota impact on skin immunity and tissue repair

The microbiota plays a fundamental role in the induction, training and function of the host immune system. In return, the immune system has evolved as a means to maintain the symbiotic relationship of the host with the microbiota. However, how the microbiota is sensed by the immune system and the defining properties of immune responses to these microbial partners remains poorly understood. Here we show that a commensal can induce antigen-specific T cell responses in a manner restricted to non-classical MHC Class I molecules. These responses are uncoupled from inflammation, and commensal-specific T cells are highly distinct from pathogen induced T cells and express a unique and complex gene signature. Notably these cells express effector genes together with strong immunoregulatory and tissue repair signatures. As such, immune responses to the commensal Staphylococcus epidermidis not only promoted heterologous protection to pathogens but also accelerated skin wound closure. These data uncover a highly physiological and pleiotropic form of adaptive immunity induced by the microbiota that couples antimicrobial function with tissue repair. Further, these results demonstrate that non-classical MHC Class I molecules, an evolutionarily ancient arm of the immune system, can function to present commensal derived antigens to T cells, supporting the idea that these pathways may have emerged as early mediators of host-microbiota interaction.