Age-Associated Remodeling of Thymopoiesis: Role for Gonadal Hormones and Catecholamines

Abstract

The present review summarizes recent data on age-related thymic changes termed thymic involution, and highlights the putative role of perturbances in extrathymical and, possibly, intrathymical production of gonadal steroids and catecholamines in this process. Thymic involution has been envisaged as an extremely complex process involving multifactorial mechanisms along the bone marrow-thymic axis that accounts for the major manifestations of immunosenescence. These mechanisms include basic cell aging processes (for example, cell replication and programmed cell death) and processes unique to the immune system (such as generation of the T cell receptor repertoire and control of potentially autoreactive cells). Given that the onset of age-associated thymic involution coincides with the rise in gonadal steroid levels at puberty, a causal link between these events has been suggested. It has been shown that: (1) peripubertal gonadectomy causes substantial decrease in the level of noradrenaline in adult male and female thymus and (2) catecholamines, acting via α- and β-adrenoceptor, produce suppressive effects on the thymic cellularity and production of both effector and regulatory T cells. Furthermore, the possibility that gonadal steroids contribute to thymic involution is discussed in this paper. In light of recent data indicating that effects of gonadal hormone deprivation on the thymic cellularity and function are long lasting but transitory, a putative role for the intrathymic sex steroid/catecholamine production in assuring the organ involution, under conditions of their limited supply by extrathymic sources, is also considered.

Androgens Contribute to Age-Associated Changes in Peripheral T-Cell Homeostasis Acting in a Thymus-Independent Way

“…Thus, our findings further support the hypothesis that androgens are important in the initial peripubertal stage of thymic involution, whereas the latter offer some other nontesticular hormone-dependent mechanisms (e.g. intrinsic thymocyte and/or thymic epithelial cell changes, alterations in circulating levels of some cytokines and hormones) to provide its maintenance and progression [reviewed in [7]]. In addition, it suggests that in the absence of testicular hormones these proinvolutive mechanisms become more efficient.…”

“…This process precedes the chronobiological deterioration of immune function, and it has been causally related to this phenomenon [4]. Given that the pubertal surge of sex steroids coincides with the first morphological and functional signs of the involution process, until fairly recently, gonadal steroids were considered the major contributing factors to thymic involution [6,7]. In the same line were data indicating increased thymic size in rodents following surgical ablation of testicular hormones [8,9], as well as in male mice showing inherited androgen receptor (AR) insensitivity [10].…”

“…However, subsequent reassessment of the role of androgens in thymic involution in mice [11] and rats [12] showed that the beneficial effects of androgen ablation on thymic size and cellularity are of limited duration. This led to the hypothesis that androgens contribute to the initiation of thymic involutive changes, whereas they do not have a role in the maintenance/progression of this process [13]. …”

Thymus-derived glucocorticoids mediate androgen effects on thymocyte homeostasis

“…In C57BL/6 mice the testosterone level, both in the testis and in serum, increases to a peak level between 3 and 8 wk of age, which correlates in time with a sharp drop in thymocyte nttmbers atid TC^R recombination activity (22). At the same time, thete is a decline in the TEC population, reflected as a reduced stromal expression of genes coditig for keratin 8 and the TEC transcriptional regulator EoxNl (23).…”

Neuro-endocrine-immune Crosstalk and Implications for Cancer Therapy

“…Testosterone replacement in castrated mice, on the other hand, results in thymic regression and a significant decrease in thymocyte numbers, with a shift toward expression of mature thymocyte phenotypes, a decrease in double-positive (DP) phenotype (CD4+CD8+) T cells, and a relative predominance of the CD4-CD8+ suppressor/cytotoxic over the CD4+CD8-helper phenotype T cells [28]. Potential mechanisms include acceleration of thymocyte apoptosis [34], AR-mediated induction of downregulatory cytokines such as transforming growth factor beta (TGF-β) [35], or changes in thymocyte differentiation and maturation [36].…”