Role of ovarian hormones in age-associated thymic involution revisited

Abstract

A commonly held view that ovarian hormones are causally involved in age-associated thymic involution has been recently challenged. In particular, their relevance in the progression of thymic involution has been disputed. To reassess this issue 10-month-old rats with well advanced thymic involutive changes were ovariectomized (Ovx), and after 1 month thymic cellularity, thymocyte development and levels of recent thymic emigrants (RTEs) were examined in peripheral blood and spleen. In addition, the distribution of major conventional and regulatory T-cell subsets was analyzed in the same peripheral lymphocyte compartments. Ovariectomy increased thymic weight and cellularity above the levels in both 10-month-old and age-matched controls indicating that ovarian hormone ablation not only prevented further progression of thymic involution, but also reversed it. The increased thymic cellularity was accompanied by altered thymocyte differentiation/maturation culminating in increased thymic output of naïve T cells as indicated by elevated levels of both CD4+ and CD8+ RTEs in peripheral blood and spleen. The changes in T-cell development produced: (i) a disproportional increase in cellularity across thymocyte subsets, so that relative proportions of cells at all maturational stages preceding the CD4+CD8+ T cell receptor (TCR)alphabeta(low) stage were reduced; the relative numbers of CD4+CD8+ TCRalphabeta(low) cells entering positive selection and their immediate CD4+CD8+ TCRalphabeta(high) descendents were increased, while those of the most mature CD4+CD8- and CD4-CD8+ TCRalphabeta(high) cells remained unaltered; (ii) enhanced cell proliferation across all thymocyte subsets and (iii) reduced apoptosis of cells within the CD4+CD8+ thymocyte subset. The augmented thymic output of naïve T cells in Ovx rats most likely reflected an early disinhibition of thymocyte development followed by increased positive/reduced negative selection, at least partly, due to raised thymocyte surface Thy-1 expression. The greater number of CD4+CD25+Foxp3+ cells in both thymus and peripheral blood suggested augmented thymic production of these cells. In addition, an increased CD4+/CD8+ cell ratio was found in the spleen of Ovx rats. Thus, ovarian hormone ablation led not only to increased diversity of the T-cell repertoire, but also to a new balance among distinct T-cell subsets in the periphery.