SUMMARY B lineage cells, B cells and antibody secreting cells, are important in skin-specific immunity and inflammation. However, their roles in skin immune responses were mainly attributed to their functions outside of the skin, e.g. in lymphoid tissues. Only recently, B cells were revealed as components of the skin immune system, opening- up a new field of discovery of their tasks within skin in homeostasis and disease. To date, our work discovered two main functions of skin B lineage cells: secretion of IgM and IL-10. Expression of the cytokines BAFF and APRIL in the skin establish the local niche for B lineage cells and regulate cutaneous secretion of IgM. Importantly, we recently showed that IL-10+ regulatory B cells (Bregs) that localize to the skin itself aid the resolution of psoriasiform inflammation and cutaneous hypersensitivity. We also discovered that mice deficient in secreted IgM (sIgM–/–) have ameliorated psoriasiform skin inflammation, consistent with a pro-inflammatory role for sIgM. However, IL-10+ Bregs are drastically increased, which may alternatively explain the reduced skin inflammation in sIgM–/– mice. Lack of the high affinity receptor for sIgM, FcµR, in B cells, translates into an intermediate IL-10+ phenotype in B cells relative to B cells from WT or sIgM–/– mice, suggesting that sIgM exerts an IL-10 suppressing activity directly on B cells. BCR engagement is a key requirement for IL-10 induction in B cells, and sIgM, upon binding to FcµR, is a modulator of BCR signaling strength and B cell activation. Thus, we hypothesize that sIgM is a major regulator of lL-10 induction in B cells via regulation of BCR signaling strength as a self-restraint mechanism and that sIgM levels in tissue niches like the skin (e.g. governed by local IgM secretion) may instruct or prevent Breg induction across various types of skin inflammation to modulate localized immune responses. Under this concept, the ability of a tissue to regulate IgM levels locally through expression of BAFF/APRIL or other factors would then affect the IL-10 production by B cells, thereby fine-tuning the local immune response. The goal of the proposed work is to define novel mechanisms to target skin immune responses by B lineage cells. Specifically, Aim 1 is disease-oriented and will identify the types and phases of skin inflammation amenable to regulation by IL-10+ skin Bregs and localized IgM-rich niches. We will employ both human tissues as well as mouse models of inflammatory skin diseases. Aim 2 is mechanism-oriented and will reveal the mechanism by which IgM modulates IL-10 programming in B cells focusing on the roles of sIgM-modulated BCR signaling, specificity requirements for sIgM, and sIgM-binding receptors. In summary, this proposal will reveal mechanisms that regulate Breg responses in skin as well as define novel ways to target skin Bregs therapeutically with relevance for cutaneous pathologies ranging from inflammation and infection to cancer.