Common gamma chain cytokines promote regulatory T cell development and survival at the CD4+ CD8+ stage in the human thymus

Abstract

Thymic commitment of human FOXP3⁺ regulatory T cells begins at the double-positive (DP) CD4⁺ CD8⁺ stage. In the current study, we show that interleukin-2 promotes the development of FOXP3⁺ thymocytes and enhances their survival at the DP phase. IL-2 increases the frequency of FOXP3⁺ cells and promotes the Treg phenotype after TCR-mediated positive selection at the most mature DP stage. However, it has no effect on FOXP3⁺ cells at the earlier maturation steps before positive selection. DP FOXP3⁺ thymocytes are highly susceptible to cell death but IL-2 promotes their survival. The anti-apoptotic protein BCL-2 (B Cell Lymphoma 2) is also upregulated by IL-2 at the most mature DP stage. In addition to IL-2, we identify IL-15 to have a significant role in the upregulating FOXP3 and survival of Tregs at the DP phase. IL-7 also increases the expression of BCL-2 in the DP FOXP3⁺ thymocytes. Our results indicate that common gamma chain cytokines IL-2, IL-7 and IL-15 promote the development of regulatory T cells at the most mature DP stage after TCR-mediated positive selection through suppressing cell death.

Keywords: T cells; cell differentiation; cells; cytokines; human; molecules; processes; subject; thymus; tissues.