Functional Dissection of Regulatory Myeloid Cells in Microbe-Immune Crosstalk in Skin

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PROJECT SUMMARY Establishment and maintenance of local immune homeostasis is essential for the integrity and function of body barrier tissues. This process involves partnership between the tissue and the commensal microbes inhabiting these sites. We have demonstrated that regulatory T cells (Tregs) are key to establishing immune tolerance to skin commensal bacteria, and that type 2 conventional dendritic cells (cDC2s) are a critical, understudied population that mediate the regulatory response to skin commensals. Specifically, our data suggest that cDC2s capture commensal antigens more readily and prime commensal-specific CD4+ T cells more efficiently than other DC subsets. After phagocytosing commensal bacteria, cDC2s display a mature-regulatory (mreg) phenotype and preferentially support commensal-specific Tregs via a mechanism that may involve Myd88 signaling in DCs. The work proposed here will build on our preliminary observations to investigate how commensal bacteria support the mreg phenotype of cDC2s and their ability to promote skin homeostasis through commensal-specific immune tolerance. We will use engineered skin commensal bacteria mutants, gnotobiotic and transgenic mouse models, high dimensional single cell analyses, novel tools to measure cDC2 priming of bacteria-specific CD4+ T cells and unique ex vivo systems to study human skin immune cell function. Combining these will allow us to elucidate how host receptor pathways respond co-operatively to bacterial ligands to promote immune homeostasis and in what manner these responses differ in skin disease, specifically hidradenitis suppurativa. The proposed studies will use innovative approaches to define the role of cDC2s in cutaneous immune regulation and identify the bacterial molecules and host pathways that regulate these processes. The results will enhance our understanding of how bacteria partner to support skin homeostasis, determine how this is altered in disease states, and inform future therapeutic strategies targeting host-commensal interactions.