The body is composed of various tissue microenvironments many of which are in close apposition with distinct commensal niches. We previously demonstrated that, in the gut, the microbiota was required for the induction of protective responses to pathogens. Outside of the gastrointestinal (GI) tract, the role of resident commensals had not been explored. The skin is the largest organ of the body and represents the primary interface between the host and the environment. Microbial profiling revealed the presence of highly diverse and specific commensal niches along distinct topographical sites of the skin. Our work demonstrates that the skin microbiota plays a non-redundant role in controlling skin immunity. More particularly we showed that the skin microbiota directly controls the level of activation of skin resident lymphocytes at steady state and during infection. Further in absence of commensals the frequencies of regulatory T cells is significantly increased. Consequently, we found that skin commensals promote protective immunity to dermal infection. The microbiota encodes millions of proteins each of them expressing several potential foreign antigens. This enormous antigenic load represents a tremendous challenge for barrier sites as unwanted responses against commensals can lead to severe pathological consequences. Sites colonized by commensals are also primary targets of infections. It is estimated that in the US, a child will suffer 10 to 15 diarrheal episodes on average before the age of 5. How the immune system perceives the microbiota in the context of acute infections and the consequences of these responses was unknown. We hypothesized that infections may disrupt our relationship with the microbiota and trigger the induction of effector responses against commensals. Under steady state conditions, various layers of structural and immunological mechanisms are in place to limit host contact with the microbiota and to maintain tolerogenic responses to commensals. We found that during acute mucosal infection, commensals can be found in tight contact with the gut epithelium and translocate to peripheral tissues. Using these unique tools we were able to demonstrate that during gastrointestinal (GI) infection, tolerance to commensals is lost and that microbiota-specific T cells differentiate to a Th1 inflammatory phenotype. Further, we showed that commensal-specific T cells activated during infection form bone fide memory cells that are phenotypically and functionally indistinguishable from pathogen-specific T cells4. Together our work demonstrates that during acute GI infection the segregation between the host and its microbiota is lost and that the immune response to commensals indiscriminately parallels the response to pathogenic microbes. Because of the million of putative antigen in a given microbiota and the high frequency of infections occurring in tissues colonized by commensals, our results suggest that a large fraction of the memory T cell pool is likely composed of commensal reactive cells. Further, translocation of commensals and microbial products across the gut mucosa also occurs in settings of radiotherapy, cirrhosis, chronic non-steroidal anti-inflammatory drug (NSAID) use, malnutrition and chronic inflammation. When added together with skin and lung infections, the immune system may have ample opportunities to be exposed to commensals in inflammatory settings. Our work has significant implications for understanding CD4 T cell interactions with the commensal microbiota, the nature of immune memory responses at mucosal sites, and the etiology of severe mucosal inflammatory responses.

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Linehan, Jonathan L; Harrison, Oliver J; Han, Seong-Ji et al. (2018) Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair. Cell 172:784-796.e18
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