Induced by Androgen Deprivation Augmentation of T Cell Levels and Responses

Androgen has been implicated as a negative regulator of host immune function and a factor contributing to the gender dimorphism of autoimmunity. Conversely, androgen deprivation has been suggested to potentiate male host immunity. Studies have shown that removal of androgen in postpubertal male mice produces an increase in size and cellularity of primary and peripheral lymphoid organs, and enhances a variety of immune responses. Yet, few details are known about the effect of androgen removal on T cell-mediated immunity. In this study, we demonstrate two pronounced and independent alterations in T cell immunity that occur in response to androgen deprivation, provided by castration, in postpubertal male mice. First, we show that levels of T cells in peripheral lymphoid tissues of mice are increased by androgen deprivation. Second, T cells from these mice transiently proliferate more vigorously to TCR- and CD28-mediated costimulation as well as to Ag-speciﬁc activation. In addition, androgen deprivation accelerates normalization of host T and B cell levels following chemotherapy-induced lymphocyte depletion. Such alterations induced by androgen deprivation may have implications for enhancing immune responses to immunotherapy and for accelerating the recovery of the immune system following chemotherapy. The Journal of Immunology, 2004, 173: 6098–6108. two to the cell may for mice have also been shown to produce higher levels of IL-2 and IFN- (cid:4) in response to Con A, and increased autoreactive Ab in response to mitogen (12). Additionally, studies have shown that AD may reduce host immunosuppression induced by hemorrhage (1) or burn injury (24). Thus, prompted by these observations, we set out to investigate the impact of AD on Ag/tissue-speciﬁc T cell responses in postpubertal Cx compared with Sx mice. In the present study, we show that peripheral T cells harvested from Cx mice, vaccinated with either nominal Ag (OVA) or murine prostate tumor cells (TRAMP-C1), proliferate more vigorously than Sx controls upon in vitro restimulation with OVA or TRAMP-C1 target cells (re-spectively). We further demonstrate enhanced responses by naive CD4 (cid:1) cells from Cx-DO11.10 TCR transgenic mice (compared with CD4 (cid:1) cells from Sx-DO11.10 control mice) upon ﬁrst time in vitro exposure to OVA 323–339 peptide. Similarly, T cells from Cx H-2Db (C57BL/6) mice exhibit greater MLR responses to irradiated allogeneic H-2Dd splenocytes than T cells from H-2Db Sx controls. In contrast, AD was not observed to induce peripheral T cell autoreactivity (measured by syngeneic MLR) or multiorgan T cell inﬂammation in Cx mice. Moderate levels of T cell inﬁltration, however, were observed within the prostate tissues of Cx mice, paralleling our previous observation that clinical AD raises re-stricted T cell responses in the prostate tissues of patients being treated for prostatic adenocarcinoma (33). From these observations, we conclude that AD generally facilitates host Ag/tissue-speciﬁc T cell responses. The facilitation of T cell responses by AD, however, is insufﬁcient to produce generalized autoimmunity, but may contribute to the development of T cell-mediated inﬂam-matory