Interleukin 2 Signaling Is Required for CD4+ Regulatory T Cell Function

Abstract

Mice deficient in interleukin (IL)-2 production or the IL-2 receptor α or β chains develop a lethal autoimmune syndrome. CD4+ regulatory T cells have been shown to prevent autoimmune diseases, allograft rejection, and to down-regulate antibody responses against foreign antigens. To assess the role of IL-2 in the generation and function of regulatory T cells, we transferred CD4+ T cells from mice genetically deficient in IL-2 or IL-2Rα (CD25) expression. A small number of splenic or thymic CD4+ T cells from IL-2 knockout mice can protect mice from spontaneous experimental autoimmune encephalomyelitis (EAE). In contrast, splenic or thymic CD4+ T cells from CD25 knockout donor mice conferred little or no protection. We conclude that T cells with regulatory potential can develop, undergo thymic selection, and migrate to the peripheral lymphoid organs in the absence of IL-2, and do not protect from disease by means of IL-2 secretion. However, IL-2 signaling in regulatory T cells is essential for their protective function. Altogether, our results favor a model whereby IL-2 induces regulatory T cell activity.

Expansion of CD4+CD25+and FOXP3+ Regulatory T Cells during the Follicular Phase of the Menstrual Cycle: Implications for Human Reproduction

“…suppressive activity of Tregs (31,32). There is also a distinct IL-2 receptor signaling pattern in CD4 ϩ CD25 ϩ Tregs compared with activated T lymphocytes in which the Janus/kinase/STAT pathway remains intact while downstream targets of the PI3K are not activated (33).…”

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

“…In addition, they also express a unique intracellular protein, Foxp3. Treg cells are completely absent in mice that are deficient in the genes encoding IL-2, IL-2Rα, IL-2Rβ and Foxp3, suggesting a crucial role for both IL-2 signaling and Foxp3 expression in Treg-cell ontogeny and survival [49][50][51]. The role of Treg cells in maintaining immunological tolerance to self-Ags has been illuminated, in part, through adoptive transfer experiments.…”

Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL‐)two to tango

“…This unexpected pathology can be explained by a reduced number of Treg or their functional impairment [24][25][26][27][28][29], since transfer of wildtype Treg into neonatal IL-2R-deficient mice prevents disease development [24,26,28,30]. IL-2 mainly plays a role for the peripheral expansion and maintenance of Treg [1,18,31] rather than their thymic generation since Treg develop in IL-2-deficient mice [16,28].…”

“…Recent in vitro studies show that IL-2 enhances Treg suppressive activity [5,13,15,16]. Furthermore, the blockade of Treg uptake of IL-2 during in vitro co-culture with responder T cells abrogates suppression [14,15] showing that IL-2 uptake by Treg is essential for suppression.…”

“…Recent data indicate that IL-2 is critical for the activation of Treg effector function, such as production of IL-10. Since Treg do not produce IL-2 they seem to depend on their capacity to efficiently compete for IL-2 with their target T cells -activated dendritic cells or conventional T cells [5,[13][14][15][16][17].…”