Dysregulation of T-Cell Development in Adrenal Glucocorticoid-Deprived Rats

Abstract

A number of different experimental approaches have been used to elucidate the impact of basal levels of adrenal gland-derived glucocorticoids (GCs) on T cell development, and thereby T cell-mediated immune responses. However, the relevance of the adrenal GCs to T cell development is still far from clear. This study was undertaken to explore the relevance of basal levels of GCs to T cell differentiation/maturation. Eight days post-adrenalectomy in adult male rats the thymocyte yield, apoptotic and proliferative rate and the relationship amongst major thymocyte subsets, as defined by TCRalphabeta/CD4/CD8 expression, were examined using flow cytometry. Adrenal GC deprivation decreased thymocyte apoptosis and altered the kinetics of T cell differentiation/maturation. In the adrenalectomized rats there was increased thymic hypercellularity and an over-representation of the CD4+CD8+ double positive (DP) TCRalphabeta(low) cells entering selection, as well as increased numbers of their DP TCRalphabeta(-) immediate precursors. These changes were accompanied with under-representation of the postselected DP TCRalphabeta(high) and the most mature CD4-CD8+ and, particularly, CD4+CD8- single positive (SP) TCRalphabeta(high) cells. This data suggests that withdrawal of adrenal GCs produces alterations in the thymocyte selection processes, possibly affecting the diversity of functional T cell repertoire and generation of potentially self-reactive cells as indicated by the reduced proportion and number of CD4-CD8- double negative TCRalphabeta(high) cells. In addition, it indicates that GCs influence the post-selection maturation of thymocytes and plays a regulatory role in controlling the ratio of mature CD4+CD8-/CD4-CD8+ SP TCRalphabeta(high) cells.

Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 Suppresses Lymphocyte Generation and Immune Responses in Mice by Increasing Plasma Corticosterone

“…Importantly, adrenalectomy induced thymic hyperplasia, as previously reported (compare Table 1 and Table 2, p<0.05, Ref. [29]). Results showed that adrenalectomized mice displayed a lack of response in the thymus to SU5416.…”

Glucocorticoids, master modulators of the thymic catecholaminergic system?

“…Since the adrenaline level in adult rat thymus has been found to be below detection level (18), it may be assumed that the thymic changes in Adx rats mainly reflected a lack of adrenal GCs. This view is further supported by data showing that: i) noradrenergic nervous fibers represent the main source of CAs in the thymus (7,8), and ii) surgical stress does not affect any of the thymopoiesis parameters analyzed (12). The ineffectiveness of propranolol in enhancing thymocyte proliferation in the absence of adrenal GCs may be explained by the fact that thymocyte proliferation was measured in an unfractionated thymocyte suspension.…”

“…In conclusion, the present study pointed to GC-dependent plasticity of CA-mediated fine-tuning of thymopoiesis, and indirectly suggested that GCs influence T-cell development, not only by a direct action on thymocytes and thymic non-lymphoid cells (11,12), but also indirectly, affecting CA availability and/or AR sensitivity to CA signaling.…”

ACTH controls thymocyte homeostasis independent of glucocorticoids

“…1 B ). Although ACTH seems to play an important role in thymocyte expansion at low GC concentrations, a role for GCs in this process may not be excluded because other reports have shown reduced apoptotic activity in the thymus following ADX (31, 32). However, at the time point we studied ADX effect on thymocyte homeostasis, we did not observe an altered basal apoptotic rate in wt mice (Supplemental Fig.…”