Androgen Receptors in Thymic Epithelium Modulate Thymus Size and Thymocyte Development*

TLDR

Castration enlarges the thymus and androgen replacement reverses this, and Tfm mice also show enlargement, indicating that androgen receptor signaling—though the cellular targets are unclear—likely mediates thymic size regulation. Immunohistochemistry and hormone‑binding assays confirmed androgen receptor expression in thymic epithelial cells, and chimeric mice with AR restricted to either lymphoid or epithelial compartments revealed the functional role of epithelial AR. Mice with AR‑positive epithelium but AR‑negative thymocytes maintained normal thymus size and androgen responsiveness, whereas mice with AR‑negative epithelium and AR‑positive thymocytes exhibited thymic enlargement and androgen insensitivity, demonstrating that epithelial AR are critical modulators of thymocyte development.

Abstract

Castration of normal male rodents results in significant enlargement of the thymus, and androgen replacement reverses these changes. Androgen-resistant testicular feminization (Tfm) mice also show significant thymus enlargement, which suggests that these changes are mediated by the androgen receptor (AR). The cellular targets of androgen action in the thymus are not known, but may include the lymphoid cells (thymocytes) as well as nonlymphoid epithelial cells, both of which have been believed to express AR. In the present study immunohistochemical analysis and hormone binding assays were used to demonstrate the presence of AR in thymic epithelial cells. The physiological significance of this epithelial cell AR expression was defined by further studies performed in vivo using chimeric mice, produced by bone marrow transplantation, in which AR expression was limited to either lymphoid or epithelial components of the thymus. Chimeric C57 mice engrafted with Tfm bone marrow cells (AR+ epithelium and AR− thymocytes) had thymuses of normal size and showed the normal involutional response to androgens, whereas chimeric Tfm mice engrafted with C57 bone marrow cells (AR− epithelium and AR+ thymocytes) showed thymus enlargement and androgen insensitivity. Furthermore, phenotypic analyses of lymphocytes in mice with AR− thymic epithelium showed abrogation of the normal responses to androgens. These data suggest that AR expressed by thymic epithelium are important modulators of thymocyte development.