Ets1 is emerging as a key transcription factor that is required to prevent autoimmunity in mice and humans. Ets1 is expressed in both B and T cells, and mice lacking Ets1 are characterized by excess B and T cell activation, leading to enhanced formation of Ab-secreting cells and high titers of autoantibodies. In humans, genome-wide association studies have detected associations of single nucleotide polymorphisms in the human ETS1 gene with autoimmune diseases, including lupus. An increased fraction of CD4 + T cells from Ets1 2/2 mice have an activated effector-memory phenotype, and there are aberrations in differentiation that contribute to the autoimmune phenotype. In vitro studies of B cells suggest that Ets1 may have B cell-intrinsic effects as well. To confirm B cell-intrinsic roles for Ets1, we crossed CD19-Cre mice to mice with a floxed allele of Ets1. Mice with a B cell-specific deletion of Ets1 show increases in B cell activation, numbers of Ab-secreting cells, and levels of autoantibodies, despite the fact that T cells are normal. However, when compared with conventional Ets1 knockout mice, mice with B cell-specific loss of Ets1 have a significantly milder phenotype. These results demonstrate that Ets1 is required in B cells to prevent autoimmune responses but that loss of Ets1 activity in other cell types is required for maximal autoimmune phenotypes. ImmunoHorizons, 2019, 3: 331-340.

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.

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.

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.

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.