Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation

• Type of Material: Article
• Authors: Haydn Kissick, Emory University; Martin Sanda, Emory University; Laura K. Dunn, Beth Israel Deaconess Medical Center; Kathryn L. Pellegrini, Harvard University; Seung T. On, Beth Israel Deaconess Medical Center; Jonathan K. Noel, Beth Israel Deaconess Medical Center; Mohamed S. Arredouani, Beth Israel Deaconess Medical Center
• Language: English
• Date: 2014-07-08
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: PNAS
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1402468111
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 111
• Issue: 27
• Start Page: 9887
• End Page: 9892
• Grant/Funding Information: This work was supported by the Prostate Cancer Foundation (PCF) Mazzone Challenge award (to M.G.S. and M.S.A.), the NIH Grant UO1-CA113913 (to M.G.S.), a PCF Young Investigator Award and Department of Defense Grant W81XWH-09-1-0448 (to M.S.A.), and Department of Defense Grant W81XWH-13-1-0246 and PCF Young Investigator award (to H.T.K.).
• Keywords: REVEALS; TESTOSTERONE; Science & Technology - Other Topics; Science & Technology; MICE; prostate neoplasm; RECEPTORS; PROTEIN-TYROSINE-PHOSPHATASE; Multidisciplinary Sciences; SEX-DIFFERENCES; ACTIVATION; immunomodulation; PTP1B; RESPONSES; PROSTATE-CANCER; cancer immunotherapy
• Research Categories: Gender Studies; Health Sciences, Immunology; Biology, Molecular; Biology, Genetics; Health Sciences, Oncology

Abstract

The hormonal milieu influences immune tolerance and the immune response against viruses and cancer, but the direct effect of androgens on cellular immunity remains largely uncharacterized. We therefore sought to evaluate the effect of androgens on murine and human T cells in vivo and in vitro. We found that murine androgen deprivation in vivo elicited RNA expression patterns conducive to IFN signaling and T-cell differentiation. Interrogation of mechanism showed that testosterone regulates T-helper 1 (Th1) differentiation by inhibiting IL-12-induced Stat4 phosphorylation: in murine models, we determined that androgen receptor binds a conserved region within the phosphatase, Ptpn1, and consequent up-regulation of Ptpn1 then inhibits IL-12 signaling in CD4 T cells. The clinical relevance of this mechanism, whereby the androgen milieu modulates CD4 T-cell differentiation, was ascertained as we found that androgen deprivation reduced expression of Ptpn1 in CD4 cells from patients undergoing androgen deprivation therapy for prostate cancer. Our findings, which demonstrate a clinically relevant mechanism by which androgens inhibit Th1 differentiation of CD4 T cells, provide rationale for targeting androgens to enhance CD4-mediated immune responses in cancer or, conversely, for modulating androgens to mitigate CD4 responses in disorders of autoimmunity.