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Abstract
A sex bias exists in major autoimmune diseases with females suffering from increased susceptibility compared to males. The male sex hormones—androgens—have been implicated in contributing to protection from autoimmunity, but cellular and molecular mechanisms underpinning androgen-mediated suppression of autoimmunity remained unclear. Here, we define the canonical androgen signaling pathway through the androgen receptor (AR) in T cell-intrinsic fashion to be sufficient in dampening α β T cell autoreactivity in the NOD/ShiLtJ (NOD) mouse model of spontaneous type I diabetes (T1D). Mechanistically, T cell-intrinsic AR signaling modulated capacity of CD8 + T cells to proliferate and secrete IFN γ in an antigen-specific manner. Moreover, we reveal that androgens influence the shaping of the thymic TCR repertoire and function of autoimmune regulator (AIRE) in a T cell-extrinsic fashion. An analysis of AR targets in T cells identified Ptpn22, a gene encoding a lymphoidspecific phosphatase that negatively regulates T cell activation, as a candidate player for AR-mediated regulation of male protection from autoimmunity. PTPN22 deletion resulted in the loss of gender bias in the B6.NZM mouse model of systemic lupus erythematosus (SLE). In addition, mutagenesis of the newly identified AR binding site in the regulatory region of Ptpn22 by CRISPR/Cas9 in NOD mice yielded generation of more aggressive autoimmune T cells. However, T cell-intrinsic AR signaling or AR-mediated modulation of Ptpn22 alone was not sufficient to establish male protection from spontaneous T1D in NOD mice. In humans, the penetrance of autoimmunity-associated mutation in PTPN22 (R620W) was found to inversely correlate with the degree of a disease sexual dimorphism, and no sex-dependent difference in the frequency of the mutant allele was detected in patients with autoimmunity. Collectively, our data supports a possibility that PTPN22 most common ’normal’ allele does contribute to disease development in a hormone dependent manner, making this protein, as well as potentially multiple other proteins that are controlled by androgens, a valid target for therapeutic interventions. Furthermore, our findings warrant investigation of additional networks and cell types that contribute to protection from autoimmunity in sex-dependent manner.