Androgens contribute to sex bias of autoimmunity in mice by T cell-intrinsic regulation of Ptpn22 phosphatase expression

Jean Lee, Leonid A. Yurkovetskiy, Derek Reiman, Lara Frommer, Zoe Strong, Anthony Chang, George J. Kahaly, Aly A. Khan () and Alexander V. Chervonsky ()
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Jean Lee: The University of Chicago
Leonid A. Yurkovetskiy: The University of Chicago
Derek Reiman: Toyota Technological Institute at Chicago
Lara Frommer: Johannes Gutenberg University (JGU) Medical Center
Zoe Strong: The University of Chicago
Anthony Chang: The University of Chicago
George J. Kahaly: Johannes Gutenberg University (JGU) Medical Center
Aly A. Khan: The University of Chicago
Alexander V. Chervonsky: The University of Chicago

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Autoimmune diseases such as systemic lupus erythematosus (SLE) display a strong female bias. Although sex hormones have been associated with protecting males from autoimmunity, the molecular mechanisms are incompletely understood. Here we report that androgen receptor (AR) expressed in T cells regulates genes involved in T cell activation directly, or indirectly via controlling other transcription factors. T cell-specific deletion of AR in mice leads to T cell activation and enhanced autoimmunity in male mice. Mechanistically, Ptpn22, a phosphatase and negative regulator of T cell receptor signaling, is downregulated in AR-deficient T cells. Moreover, a conserved androgen-response element is found in the regulatory region of Ptpn22 gene, and the mutation of this transcription element in non-obese diabetic mice increases the incidence of spontaneous and inducible diabetes in male mice. Lastly, Ptpn22 deficiency increases the disease severity of male mice in a mouse model of SLE. Our results thus implicate AR-regulated genes such as PTPN22 as potential therapeutic targets for autoimmune diseases.

Date: 2024
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DOI: 10.1038/s41467-024-51869-7

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