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* Surgery Branch, Center for Cancer Research, National Cancer Institute;
Ghost Laboratory, Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases;
Metabolism Branch, Center for Cancer Research, National Cancer Institute; and
Howard Hughes Medical Institute Research Scholars Program, National Institutes of Health, Bethesda, MD 20892
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-2R
(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.
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