Androgen receptor regulation of CD8 T cell immune responses

Abstract Sex differences in disease susceptibility, including infection, cancer, and autoimmunity, have been characterized, with males generally more susceptible to infections and malignancies, and females to autoimmune diseases. While many factors underlie such differences, sex differences in T cell differentiation and function likely lead to disparate adaptive immune responses and disease control. Indeed, sex hormones, including androgens, are strong regulators of gene expression, and have been implicated as drivers of inflammation and regulators of T cell differentiation, but the mechanisms of such control remain unknown. We reveal that androgen receptor (AR) activity in CD8 T cells suppresses activation and reduces proliferation and effector function. We show that anti-CD3- and anti-CD28-activated or peptide-pulsed CD8 T cells exhibit enhanced proliferation, effector cytokine production, activation marker expression, and altered histone modifications upon treatment with AR inhibitors or genetic AR deletion. Further, we demonstrate ligand-dependent AR binding to genetic loci of effector and differentiation genes in CD8 T cells via chromatin immunoprecipitation and quantitative PCR. Finally, in vivo murine models of lymphocytic choriomeningitis virus reveal an increase in AR mRNA expression in virus-specific CD8 T cells following infection, which persists in memory cells and during chronic infection. These data suggest that AR regulates epigenetic and transcriptional changes induced during T cell activation and differentiation, thereby dampening the T cell response. Therefore, disruption of AR activity in T cells may be a viable therapeutic approach for altering the T cell response in the context of human diseases. Supported by grants from NIH (NRSA T32 5T32GM71338-15, NRSA T32 1T32GM142619-01), Knight Cancer Institute (Knight Pilot Award), and OHSU Foundation