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Roles Of CCR10 in establishment and maintenance of skin T cell homeostasis

Fu, Y;

Skin, the largest organ of a human body, encounters a host of various environmental agents. To maintain the integrity and function of the skin, immune cells in the skin are tightly regulated to allow tolerance to harmless antigens but mount effective response to dangerous assaults, and their dysregulation might increase incidence of skin diseases. Balanced presence of different types of immune cells in the skin is critical in protecting against foreign assaults and preventing inflammatory damage. However, how immune cell homeostasis is established and maintained in skin is not well understood. CCR10, with its ligand CCL27 expressed by keratinocytes, are the most skin-specific chemokine/receptor pair implicated in the skin T cell migration and inflammatory diseases. Skin-resident T cells are unique populations of immune cells with memory cell–like properties. Among them, recently identified skin-resident CD8+ memory T (Trm) cells play an important role in providing faster immune responses to skin infection than those from the circulation. However, it remains elusive that how these cells persist in the skin and whether/how they regulate other immune cells in the local tissue. Using CCR10 knockout/EGFP knockin mice, I determined the role of CCR10-mediated migration of memory-like CD8+ cells and the maintenance of immune homeostasis in the skin. I found that CCR10-/- mice had imbalanced numbers and dysregulated functions of skin-resident effector and regulatory T (Teff and Treg) cells associated with enhanced innate and memory skin immune responses to antigen stimulations. The enhanced immune response in CCR10 -/- mice allowed them to clear the skin Leishmania major (L. major) infection more efficiently than wild type (WT) mice did. I also found that that skin-resident CCR10+ CD8+ T cells are important in the homeostasis of resident ILCs and CD4+ T cells by promoting the maintenance of regulatory T (Treg) cells in the skin through the B7.2/CTLA-4 axis to promote immune homeostasis and control immune responses. Specifically, impaired establishment of CCR10-knockout CD8+ resident T cells in the skin results in enhanced immune responses to both T cell antigen specific and non-specific challenges. The over-active response is associated with altered balance of resident Treg and CD4+ effector T (Teff) cells. Further studies found that B7.2 expressed on CD8+ T cells is involved in supporting Treg cells in the skin through interaction with CTLA-4 highly expressed on skin Treg cells. These findings provide novel insight into mechanisms regulating immune homeostasis and responses in the local tissue that could help in areas such as vaccine development and therapeutic design for treatment of chronic inflammatory diseases.