Critical influence of the thymus on peripheral T cell homeostasis

A tight balance between regulatory CD4⁺Foxp3⁺ (Treg) and conventional CD4⁺Foxp3^- (Tconv) T cell subsets in the peripheral compartment, maintained stable throughout most of lifetime, is essential for preserving self-tolerance along with efficient immune responses. An excess of Treg cells, described for aged individuals, may critically contribute to their reported immunodeficiency. In this work, we investigated if quantitative changes in thymus emigration may alter the Treg/Tconv homeostasis regardless of the aging status of the peripheral compartment.

We used two different protocols to modify the rate of thymus emigration: thymectomy of adult young (4-6 weeks old) mice and grafting of young thymus onto aged (18 months old) hosts. Additionally, lymphoid cells from young and aged B6 mice were intravenously transferred to B6.RAG2 mice. Alterations in Treg and Tconv peripheral frequencies following these protocols were investigated after 30 days by flow cytometry.

Thymectomized young mice presented a progressive increase in the Treg cell frequency, while the grafting of a functional thymus in aged mice restored the young-like physiological Treg/Tconv proportion. Strikingly, T cells derived from young or aged splenocytes colonized the lymphopenic periphery of RAG^-/- hosts to the same extent, giving rise to similarly elevated Treg cell levels irrespective of the age of the donor population. In the absence of thymus output, the Treg subset seems to survive longer, as confirmed by their lower proportion of Annexin-V⁺ cells.

Our data suggest that the thymus-emigrating population, harboring an adequate proportion of Treg/Tconv lymphocytes, may be essential to keep the Treg cell balance, independently of age-related shifts intrinsic to the peripheral environment or to the T cell biology.