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

Significance Testosterone has been implicated as a regulator of the immune response to viruses, vaccines, host tissue, and cancer. Despite this pleiotropic effect on the immune system, the mechanisms underlying this effect are not well understood. In this study, we investigated how testosterone altered gene expression and signaling mechanisms in CD4 T cells in mouse models and prostate cancer patients undergoing androgen deprivation therapy. We found that testosterone inhibited T-helper 1 differentiation by up-regulating the phosphatase, Ptpn1, in both mice and humans. Additionally, the androgen receptor bound a highly conserved region of the Ptpn1 gene, suggesting an evolutionarily important purpose of this mechanism. This study provides a mechanism to explain recent discoveries regarding the role of testosterone-mediated inhibition of the immune response. 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.

[1]  Mark M. Davis,et al.  Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination , 2013, Proceedings of the National Academy of Sciences.

[2]  Leah M. Feazel,et al.  Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity , 2013, Science.

[3]  T. Midoro-Horiuti,et al.  Estrogen effects in allergy and asthma , 2013, Current opinion in allergy and clinical immunology.

[4]  Nathan C. Sheffield,et al.  Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity , 2012, Genome Biology.

[5]  A. Baniahmad,et al.  Androgen receptor-mediated gene repression , 2012, Molecular and Cellular Endocrinology.

[6]  L. Lessard,et al.  PTP1B is an androgen receptor-regulated phosphatase that promotes the progression of prostate cancer. , 2012, Cancer research.

[7]  M. Tremblay,et al.  PTP1B Deficiency Exacerbates Inflammation and Accelerates Leukocyte Trafficking In Vivo , 2012, The Journal of Immunology.

[8]  M. Sanda,et al.  Androgen ablation augments human HLA2.1‐restricted T cell responses to PSA self‐antigen in transgenic mice , 2010, The Prostate.

[9]  Andrew Pekosz,et al.  The Xs and Y of immune responses to viral vaccines. , 2010, The Lancet. Infectious diseases.

[10]  Y. Wan,et al.  How diverse--CD4 effector T cells and their functions. , 2009, Journal of molecular cell biology.

[11]  D. Levy,et al.  Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells , 2009, Immunology.

[12]  W. Carr,et al.  Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses. , 2008, Archives of internal medicine.

[13]  I. Lossos,et al.  PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling. , 2008, Blood.

[14]  M. P. Muehlenbein,et al.  Testosterone correlates with Venezuelan equine encephalitis virus infection in macaques , 2006, Virology Journal.

[15]  C. Drake,et al.  Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. , 2005, Cancer cell.

[16]  A. Keegan,et al.  Abnormal Th1 Cell Differentiation and IFN-γ Production in T Lymphocytes from Motheaten Viable Mice Mutant for Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-11 , 2005, The Journal of Immunology.

[17]  B. Leibovich,et al.  Augmentation of T Cell Levels and Responses Induced by Androgen Deprivation1 , 2004, The Journal of Immunology.

[18]  Chao A. Hsiung,et al.  Single nucleotide polymorphisms in protein tyrosine phosphatase 1beta (PTPN1) are associated with essential hypertension and obesity. , 2004, Human molecular genetics.

[19]  R. Olshen,et al.  Single nucleotide polymorphisms in protein tyrosine phosphatase 1beta (PTPN1) are associated with essential hypertension and obesity. , 2004, Human molecular genetics.

[20]  G. Cooper,et al.  The epidemiology of autoimmune diseases. , 2003, Autoimmunity reviews.

[21]  T. Mustelin,et al.  SHP2 regulates IL-2 induced MAPK activation, but not Stat3 or Stat5 tyrosine phosphorylation, in cutaneous T cell lymphoma cells. , 2002, Cytokine.

[22]  F. Wunderlich,et al.  Developmental regulation of intracellular and surface androgen receptors in T cells , 2002, Steroids.

[23]  D. Barford,et al.  TYK2 and JAK2 Are Substrates of Protein-tyrosine Phosphatase 1B* , 2001, The Journal of Biological Chemistry.

[24]  M. T. Moser,et al.  T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  N. Aoki,et al.  A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b* , 2000, The Journal of Biological Chemistry.

[26]  S. Burakoff,et al.  Cytosolic Tyrosine Dephosphorylation of STAT5 , 2000, The Journal of Biological Chemistry.

[27]  B. Kennedy,et al.  Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. , 1999, Science.

[28]  H. Mossmann,et al.  Functional testosterone receptors in plasma membranes of T cells , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  B. Neel,et al.  The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its 35 amino acid C-terminal sequence , 1992, Cell.

[30]  E. Krebs,et al.  Microinjection of a protein-tyrosine-phosphatase inhibits insulin action in Xenopus oocytes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[31]  B. Neel,et al.  Cloning of a cDNA for a major human protein-tyrosine-phosphatase. , 1990, Proceedings of the National Academy of Sciences of the United States of America.