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PROJECT SUMMARY The strength of an immune response against a transplanted organ, termed the alloresponse, depends on the extent of genetic differences between the donor and the recipient and their recognition by the recipient?s immune system. Our studies from the previous funding cycle have shown that the microbiota, the collection of microbes that colonize the body and differ between individuals, is an additional novel factor that can causally modulate the intensity and kinetics of the alloresponse to a transplanted organ. Unlike donor and host genetics, the microbiota can be manipulated therapeutically, thus providing possible new interventions to protect the graft and help reduce the need for immunosuppressive drugs that can cause significant side effects. We initially considered the body?s microbiota as a whole and demonstrated that a reduction in microbial diversity induced by broad-spectrum antibiotic (Abx) pre-treatment, or an absence of microbiota using germ-free (GF) mice, both improved minor mismatched skin graft survival. Fecal microbiome transfer (FMT) from control, but not Abx-pre-treated mice, into GF mice was sufficient to accelerate skin graft rejection. This demonstrated both the causality of the microbiota on affecting graft outcome, and the divergent effects of distinct fecal microbial communities. Abx pre-treatment also delayed rejection of fully mismatched skin grafts, minor mismatched lung grafts, and MHC class II-mismatched heart grafts, indicating that whole-body microbiota affects the outcome of both colonized and sterile organs. We further showed that that some microbial communities could be dominantly protective of rejection. This protection was associated with fecal presence of bacteria of the genus Alistipes. In addition, the half-life of small bowel, lung and skin transplants is much shorter than that of heart and kidney grafts, supporting the hypothesis that the commensals in the graft may also be able to influence alloimmunity. Our recent preliminary experiments demonstrate that colonization of donor skin with the single commensal Staphylococcus epidermidis (S. epi), in the absence of intestinal colonization of the host, can be sufficient to accelerate skin graft rejection. This result clearly demonstrates that microbiota within the allograft also impacts graft outcome. Notably, the mechanism by which skin S. epi accelerates skin graft rejection appears different from how whole-body microbiota in SPF mice or FMT into GF mice accelerates skin graft rejection. We hypothesize a novel paradigm that the recipient gut microbiota affects immune responses in the whole animal by systemically modulating DCs up or down, whereas the microbiota in the donor graft locally affects the effector phase of the alloresponse upon migration of recipient alloreative T cells into the graft. Using a combination of TCR transgenic T cells and p:MHC multimers to track anti-commensal and anti-donor immune responses in parallel, as well as select bacterial colonization of distinct tissues in gnotobiotic mice, we will: 1. Investigate the mechanisms by which gut-only microbes can impact skin graft rejection distally; 2. Define the mechanisms by which skin-only commensals locally accelerate skin graft rejection.