Androgen Modulates Thymopoiesis by Regulating Thymocyte Precursor Immigration.

Impaired thymopoiesis contributes to immune deficiency in aging, AIDS, and following allogeneic bone marrow transplantation. However, little is known of the mechanisms of thymic regulation and the determinants of thymic function. Exogenous administration of testosterone and estrogen has been shown to accelerate thymic involution. Conversely, studies have demonstrated that castration of male mice resulted in increased thymic size and thymocyte number. We present data that thymic enlargement in castrated male mice is due to enhanced thymopoiesis. Comparing castrated post-pubertal male mice with age-matched control littermates, we found a statistically significant doubling of thymic weight, thymocyte number, and double-positive CD4+CD8+ thymocytes as early as eight days post-orchiectomy. Major thymocyte subsets defined as CD4− CD8−, CD4+CD8−, CD8+CD4− were also increased post castration and the ratio of subsets was unchanged suggesting that castration augmented overall thymic activity. This was further corroborated by a concomitant 4–6 fold increase in thymic T cell-receptor excision circles (TREC). Significantly, at one month post-castration, early thymic progenitors (Lin- CKIT hi CD44 hi) were increased threefold in the castrated cohort. The increase in thymic productivity led to a subsequent increase in peripheral cell populations, with a significant increase in splenic CD4+ and CD8+ T cells. The greatest proportion of this increase was due to naïve splenic CD4 and CD8 T cells total numbers as defined by CD44lo expression. Memory splenocytes, CD44hi CD4+ and CD8+ cells, were slightly increased as well. Additionally, there was an increase in the number of splenic recent thymic emigrants (RTE) as enumerated by TREC. Our data suggest that androgen withdrawal leads to an increase in thymopoiesis, as enumerated by a significant influx of ETPs, increased total thymic TREC, subsequent increases in single positive thymocytes, and increased peripheral recent thymic emigrants. Furthermore, the data suggest that a mechanism by which this occurs is through increased immigration of thymocyte precursors from the bone marrow into the thymus identifying this as a central point in thymic regulation.