title: Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation.
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.
authors: Urology Division, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors: Haydn T
authors: HT
authors: Kissick
authors: Department of Urology, Emory University School of Medicine, Atlanta, GA 30322; and.
authors: Martin G
authors: MG
authors: Sanda
authors: Urology Division, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors: Laura K
authors: LK
authors: Dunn
authors: Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215.
authors: Kathryn L
authors: KL
authors: Pellegrini
authors: Urology Division, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors: Seung T
authors: ST
authors: On
authors: Urology Division, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors: Jonathan K
authors: JK
authors: Noel
authors: Urology Division, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; marredou@bidmc.harvard.edu.
authors: Mohamed S
authors: MS
authors: Arredouani
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D018664:Interleukin-12 / Q000494:pharmacology; D007422:Intestines / Q000166:cytology; D007438:Introns; D008168:Lung / Q000166:cytology; D008297:Male; D051379:Mice; D009919:Orchiectomy; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D053634:TYK2 Kinase / Q000378:metabolism; D013739:Testosterone / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology*; D015854:Up-Regulation
chemical_list: D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D018664:Interleukin-12; D013739:Testosterone; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
keywords: cancer immunotherapy; immunomodulation; prostate neoplasm