Androgen modulation of immunity to tumor antigens have implications on designing novel prostate cancer immunotherapy regimens. However, the mechanisms governing androgen action are largely unknown. Herein we compared mouse castrate and non-castrate CD4 T cell transcriptomes and revealed major perturbations in gene regulation. Ingenuity pathway analysis identified dysregulations in key pathways, including Th cell differentiation, TCR signaling, Interferon signaling, and p38 MAPK signaling. Interestingly, nearly half of the genes that constitute the T cell differentiation pathway were affected. These genes include key transcription factors such as STAT1, Tbet, Foxp3, ROR-γ, costimulatory molecules CD40L and ICOS, and T helper cytokines such as IFN-γ, IL-17, TNF-α, and IL- 2. Transcription factors driving Th1 and Th17 differentiation as well as Th1 and Th17 cytokines and costimulatory receptors were upregulated. More CD4 T cells from castrated mice produced IFN-γ than did non-castrated ones. Conversely, exposure of activated CD4 T cells to IL-12 in the presence of androgens inhibited IFN-γ production and reduced Th1 differentiation genes like T-bet and IL-12-Rβ. This was concurrent with inhibition of STAT4 phosphorylation and upregulation of Ptpn22 and Ptpn1, both of which exhibit the ability to dephosphorylate STAT proteins. This suggests androgens’ negative effects on Th1 differentiation might be partly induced through Ptpn22- and Ptpn1-dependent dephosphorylation of STAT4.
- Copyright © 2013 by The American Association of Immunologists, Inc.