The role of IL-2-/IL-2r signaling for Treg cell development, homeostasis and function

CD4+ Foxp3+ regulatory T (Treg) cells belong to a distinct T cell lineage which develops in the thymus and is essential for the prevention of self-reactivity by suppressing peripheral auto-reactive T cells that escape thymic negative selection. IL-2/IL-2R signaling is crucial and non-redundant for the development of thymic Treg cells, as well as the homeostasis and competitive fitness of peripheral Treg cells. The central role of IL-2 in Treg biology is exemplified by the uncontrolled massive lymphoproliferation associated with IL-2-/-, IL-2Rα-/- and IL-2Rβ-/- mice which typically die by 4-12 week of age. It is noteworthy that a restored normal percentage and number of peripheral Treg cells in Bim-/- IL-2-/- mice did not rescue these mice from severe autoimmunity. Instead, additional IL-2 was still required for the proper functioning of peripheral Bim-/- IL-2 -/- Treg cells. Consistently, in the current studies, we found that the development of thymic Treg cells was blocked with mostly CD4+ CD25- Foxp3lo T cells in the IL-2Rβ -/- mice, and these cells were mainly defective for functional maturation. However, weak IL-2Rβ signaling associated with IL-2Rβ mutant mice largely supported normal Treg development and function in the thymus. Further examination indicated that the contribution of this weak IL-2Rβ signaling was associated with pSTAT5 activity.;Although low IL-2 signaling is sufficient for programming mature and functional thymic Treg cells prior to their populating the periphery, aged IL-2Rβ mutant mice bearing weak and transient pSTAT5 signal develop autoimmunity by involving T cell infiltration into tissue sites. In addition, gene array analysis of peripheral Treg cells with lower IL-2R signaling suggested that the expression of some molecules is IL-2 dependent, such as Klrg1. We found that Klrg1 marked a small fraction of peripheral Treg cells. They were highly activated, antigen-responsive and short-lived. Klrg1+ Treg cells were also potentiated with superior suppressive function and represented a terminally differentiated subset derived from Klrg1- Treg precursors. Importantly, the development of Klrg1+ Treg subset required extensive IL-2R signaling. This activity of IL-2 is distinct from its contribution to Treg homeostasis and competitive fitness. Overall, these properties are analogous to Klrg1 marked terminally differentiated short-lived CD8+ T effector cells. Thus, a pathway driving antigen activated conventional T lymphocytes is also similarly co-operated by Treg cells.