Androgen Receptor regulates Ptpn22.

Abstract The need to rear the offspring necessitated the evolution of female’s immune system to mount stronger responses than males. One consequence of it is that major autoimmune diseases manifest in a sex biased manner with a predominance in females. However, mechanisms underlying the bias have not been clearly defined. We investigated the molecular mechanisms by which male sex hormones (androgens) regulate αβ T cell function in sex biased autoimmunity. We identified Ptpn22, a gene encoding a lymphoid-specific phosphatase that negatively regulates proximal TCR signaling events, as a direct target of a transcription factor Androgen Receptor (AR) in T cells. In T cells isolated from sham-operated or castrated mice, transcription of Ptpn22 correlated with the presence of androgens. Furthermore, stimulation of Jurkat T cells with AR agonist resulted in induction of Ptpn22 transcription only in the presence of AR. Deletion of Ptpn22 in the B6.NZM mouse model of Systemic Lupus Erythematosus (SLE) led to exacerbation of autoimmunity accompanied by the loss of sexual dimorphism. We identified an androgen response element (ARE) in the 5′ UTR of Ptpn22 and found that its CRISPR/Cas9-mediated mutation enhanced both in vitro and in vivo the autoreactivity of T cells in NOD/ShiLtJ mouse model of Type I Diabetes (T1D). In humans, PTPN22 R620W mutation associated with several autoimmune disorders inversely correlated with the sexual dimorphism of autoimmunity. Thus, the ‘wild-type’ common allele of PTPN22 is likely to be involved in sex bias in autoimmune conditions. NIH grant R01 AI 127411