Genetic Interactions of the Transcription Factor Ets1 and IL17RA Signaling in Autoimmunity and Immunodeficiency

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 spontaneous autoimmune disease with high levels of autoantibodies. Naïve CD4+ T cells isolated from Ets1 KO mice differentiate more readily to Th17 cells that secrete IL17, a cytokine extensively implicated in autoimmune disease pathogenesis. To determine if increased IL17 production contributes to the development of 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 prevent or ameliorate the autoimmune phenotype of Ets1 KO mice, but rather that DKO animals exhibited worse symptoms with significant increases in activated B cells and secreted autoantibodies. This was correlated with a prominent increase in the numbers of T helper 2 (Th2) and T follicular helper (Tfh) cells. In addition to the autoimmune phenotype, DKO mice also showed aspects of immunodeficiency and developed spontaneous skin lesions colonized by Staphylococcal species. When DKO mice were experimentally infected with Staphylococcus aureus they were unable to clear the bacteria, despite a robust anti-staphylococcal antibody response. Persistent skin infection results in increased immune cell activation and likely contributes to the enhanced autoimmune symptoms of DKO versus Ets1 KO mice. Our studies suggest that targeting IL17RA signaling in autoimmune diseases might in some cases result in increased autoimmunity or to increased susceptibility to opportunistic infections.