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, hut also reversed it. The increased thymic cellularity was accompanied by altered thymocyte differentiation/maturation culminating in increased thymic output of nave 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)alpha beta(low) stage were reduced; the relative numbers of CD4 + CD8 + TCR alpha beta(low) cells entering positive selection and their immediate CD4 + CD8 + TCR alpha beta(high) descendents were increased, while those of the most mature CD4 + CD8 and CD4 CD8 + TCR alpha beta(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 naive 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.