The transcription factor Ets1 cooperates with IL17 signaling to promote autoimmunity and immunodeficiency.

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 spontaneous autoimmune disease with high levels of autoantibodies. Naïve CD4+ T cells isolated from Ets1 KO mice have differentiate more readily to Th17 cells and secrete IL-17, a cytokine extensively implicated in autoimmune disease pathogenesis. To determine if increased IL-17 production contributes to the development of autoimmunity in Ets1 KO mice, we generated Ets1/IL-17 Receptor double knock out (DKO) mice. We found that the absence of IL-17 signaling did not prevent or ameliorate the phenotype of Ets1 KO mice, but rather that DKO animals exhibited worse symptoms with striking increases in the numbers of Th2 cells and Tfh cells as well as germinal center B cells, isotype-switched B cells, memory B cells and plasma cells. Furthermore, DKO mice develop spontaneous skin lesions colonized by Staphylococcus aureus (S. aureus). When DKO mice were experimentally infected with S. aureus they were unable to clear the bacteria. Curiously, the increased bacterial susceptibility was age-dependent as 2 month old DKO mice were not susceptible, whereas 4 month old mice were. Our current model is that excessive immune activation over time leads to production of autoantibodies that target immune effector mechanisms important for anti-bacterial immunity, such as anti-microbial peptides, thereby resulting in susceptibility to S. aureus. Our studies may have important implications in understanding the mechanisms that drive pathogenesis in human diseases characterized by both autoimmunity and immunodeficiency.