Ets1 regulates production of dendritic epidermal T cells (DETC) and cooperates with IL17Ra signaling to regulate immune responses to Staphylococcal skin infection

Abstract

Abstract Ets1 is a lineage-specific transcription factor regulating lymphocyte differentiation. Mice that lack Ets1 (Ets1 KO) develop autoimmune disease with enhanced B and T cell activation, including increased production of IL-17. To determine if IL-17 contributes to autoimmunity, we crossed Ets1 KO mice to mice lacking the IL17 receptor A subunit (IL17RA KO) to generate double knock out (DKO) mice. We found that loss of IL17RA did not prevent or ameliorate autoimmunity, but that DKO animals exhibited worse symptoms. DKO mice also showed susceptibility to skin infections with Staphylococcal bacteria. To define the molecular mechanisms that might underlie this phenotype, we assessed gene expression in skin of DKO mice and control mice, which showed reduced expression of Skint genes. Skint proteins are involved in γδ T cell development and skin wound healing responses. We examined the presence of subsets of γδ T cells in the skin including dendritic epidermal T cells (DETC), whose role in murine wound healing responses is well described, and dermal γδ T cells that are important for anti-Staphylococcal immunity. Loss of Ets1 leads to a complete absence of DETC in the skin of mice. On the other hand, dermal γδ T cells are present in all genotypes. While DETC are absent from the skin of both Ets1 KO mice and DKO mice, only DKO mice show enhanced susceptibility to skin Staphylococcal infections, indicating that Ets1 and IL17RA regulate additional aspects of skin immunity. We propose that impaired responses to skin Staph infections in DKO mice are driven both by impaired IL17RA signaling and impaired wound healing. We further propose that the chronic bacterial infection in the skin results in enhanced immune activation and enhanced autoimmunity in DKO mice. Funded by NIH R01 AI122720 and the Lupus Research Alliance.