Glucocorticoids delay age-associated thymic involution through directly affecting the thymocytes.

Abstract

After puberty, the thymus undergoes a dramatic loss in size, resulting in a reduction in the number of thymocytes, a phenomenon termed age-associated thymic involution. The factors regulating this process are poorly understood. We investigated the role of endogenous glucocorticoids (GCs) in this process by studying transgenic mice with increased GC sensitivity restricted to the T-cell lineage due to overexpression of a GC-receptor transgene under the control of the proximal lck promoter. Surprisingly, in these transgenic mice, the age-associated thymic involution did not start until after 6 months of age, demonstrating that endogenous GCs through directly affecting the thymocytes delay the age-associated thymic involution process. The delayed age-associated thymic involution resulted in a significantly higher number of thymocytes in transgenic mice, compared with wild-type mice at 6 months of age or older. The higher number of thymocytes was associated with increased percentage of cycling double-negative and single-positive thymocytes, whereas thymic apoptosis was unaffected. The above effects of GCs were restricted to the thymocytes and were not reflected on the peripheral T cells, in which GCs suppressed the number of peripheral T cells in aged transgenic mice, demonstrating that thymocytes and T cells are differentially regulated by GCs. Furthermore, CD4(+) T cells were more affected than CD8(+) T cells, resulting in a decrease in the CD4/CD8 T-cell ratio. In summary, our results reveal novel biological effects of endogenous GCs on thymic involution and T-cell homeostasis in aged mice.