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.immunomodulation | cancer immunotherapy | prostate neoplasm

Antagonizing Peroxisome Proliferator–Activated Receptor α Activity Selectively Enhances Th1 Immunity in Male Mice

“…It has been suggested that sex differences in Th1 responses arise because of the higher IL-12 production by APC and enhanced T cell responsiveness to this cytokine in females (11,12). We previously observed that even in the absence of IL-12, male CD4 + T cells have a lower intrinsic ability than female CD4 + T cells to produce IFN-g, which associated with higher expression of PPARa (6,7).…”

“…This sex difference is thought to underlie why women generate enhanced antiviral (9) and antitumor (10) immune responses, but also have a higher propensity to develop certain autoimmune diseases (8). Past studies have suggested that sex differences in Th1 responses arise because of suppressive effects of androgens at key nodes in the Th1 differentiation pathway including IL-12 production (11) and signaling (12,13) and IFN-g production downstream of Ag stimulation (6,7). Until recently, the molecular players involved in this androgen-dependent regulation were not known.…”

Data integration for identification of important transcription factors of STAT6-mediated cell fate decisions

“…Consistent with this, a few TFs were increased by STAT6 and associated with suppressive processes in Th1, Th17, or iTreg cells. For instance, AR inhibits IL12 signaling and Th1 cell differentiation by up-regulating Ptpn1 (Kissick et al, 2014), STAT3 activation and HIF1α inhibit iTreg cell differentiation (Laurence et al, 2012;Palazon et al, 2014), and ETV6 is known as a repressor in Th17 cells (Ciofani et al, 2012). However, STAT3 can also induce Th17 cell differentiation (Zhu and Paul, 2010) and promote Th2 cell differentiation together with IL6 (Stritesky et al, 2011).…”

Clinical value of Pro‑GRP and T lymphocyte subpopulation for the assessment of immune functions of lung cancer patients after DC‑CIK biological therapy

“…The increase of CD8 + cells is beneficial for the constant growth of a tumor (18). When the tumor evades the immune system, CD4 + CD25 + Treg cells restrain the activation and proliferation of CD4 + cells by excreting IL-6 and IL-7 cell factors and inducing the activation of signal transducer and activator of transcription 4.…”