Interleukin-2-Dependent Mechanisms of Tolerance and Immunity In Vivo

Abstract

IL-2 is a critical T cell growth factor in vitro, but predominantly mediates tolerance in vivo. IL-2 is mainly produced by CD4+ Th cells, but the role of Th cell-derived IL-2 in vivo is controversial. We demonstrate that during immunity to a tumor/self-Ag, the predominant role of Th cell-derived IL-2 was to maintain IL-2Rα (CD25) on CD4+ T regulatory cells (Treg), which resulted in their maintenance of the Treg cell lineage factor, Forkhead/winged helix transcription factor (Foxp3), and tolerance. However, in the absence of Treg cells, Th cell-derived IL-2 maintained effector T cells and caused autoimmunity. IL-2R signaling was indispensable for Treg cell homeostasis and efficient suppressor function in vivo, but, surprisingly, was not required for their generation, because IL-2−/− and CD25−/− mice both contained Foxp3+ T cells in the periphery. IL-2R signaling was also important for CD8+ T cell immunity, because CD25−/− tumor-reactive CD8+ T cells failed to affect established tumors. Conversely, IL-2R signaling was not required for Th cell function. Lastly, administration of anti-IL-2 plus exogenous IL-15 to tumor-bearing mice enhanced the adoptive immunotherapy of cancer. Therefore, Th cell-derived IL-2 paradoxically controls both tolerance and immunity to a tumor/self-Ag in vivo.