IL-2 promotes the function of memory-like autoregulatory CD8+ T cells but suppresses their development via FoxP3+ Treg cells

Abstract

IL-2 plays a critical role in both effector T-cell development and FoxP3+CD4+ Treg-cell homeostasis. A reduction in Il2 transcription results in impaired FoxP3+CD4+ Treg-cell recruitment and function, and accounts for the association between murine Il2 and type 1 diabetes (T1D). The progression of T1D elicits a disease-countering negative feedback regulatory loop that involves the differentiation of low-avidity autoreactive CD8+ T cells into memory-like autoregulatory T cells in a CD4+ Th-dependent manner. Since these auto-regulatory T cells express IL-2Rβ (CD122), we hypothesized that their development might also be regulated by IL-2. Here, we investigate the effects of differences in IL-2 expression on this autoregulatory subset. We show that decreased IL-2 production impairs the regulatory capacity of memory-like autoregulatory CD8+CD122+ T cells. Surprisingly, we also find that a reduction in IL-2 production capacity increases memory autoregulatory CD8+ T-cell formation indirectly, by decreasing the development and function of FoxP3+ Treg cells in nonobese diabetic mice. These results illustrate a complex homeostatic interplay between IL-2, CD4+ Th cells, FoxP3+CD4+ Treg cells and autoregulatory CD8+ T-cell memory whereby IL-2 controls the function of both Treg-cell subsets, but IL-2-potentiation of FoxP3+CD4+ Treg-cell function results in the suppression of CD4+ Th-cell activation and autoregulatory memory CD8+ T-cell formation. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.