Loss of IL17 signaling in lupus-prone Ets1 knockout mice leads to worsened autoimmunity combined with increased susceptibility to Staphylococcal skin infections

Abstract

Abstract Ets1 is a lineage-specific transcription factor that regulates B and T cell functions in development and disease. Mice that lack Ets1 (Ets1 KO) develop autoimmune disease with high levels of autoantibodies. Naïve CD4+ T cells isolated from Ets1 KO mice differentiate more readily to IL17 producing Th17 cells. To determine if IL17 production contributes to the observed autoimmunity in Ets1 KO mice, 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 the absence of IL17RA signaling did not ameliorate the autoimmune phenotype of Ets1 KO mice. Instead, DKO animals exhibited worse symptoms with increases in activated B cells, autoantibody titers, T helper 2, and T follicular helper cells. DKO mice showed aspects of immunodeficiency, developing spontaneous skin lesions colonized by Staphylococcus xylosus. When DKO mice were infected with Staphylococcus aureus they were unable to clear the bacteria, indicating a general immunodeficiency to Staph bacteria. Gene expression analysis revealed diminished expression of the Skint gene family in DKO skin. Skint genes play important roles in the maintenance of TCRγδ+ dendritic epidermal T cells (DETC) and in skin wound healing. DKO mice had reduced numbers of DETC in the skin, which may lead to increased susceptibility to Staph infections. We propose that Staph skin infections in DKO mice leads to enhanced immune activation and enhanced autoimmunity. Our studies suggest that therapies targeting IL17RA signaling in autoimmune diseases may result in increased autoimmunity or to increased susceptibility to skin Staph infections.