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* Division of Surgery, Center for Cancer Research, National Cancer Institute, National Institutes of Health,
Ghost Lab, National Institute of Allergy and Infectious Diseases,
Laboratory of Immunology, National Eye Institute, National Institutes of Health, and
Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, National Institutes of Health, Bethesda, MD 20892;
¶ McGill University, Montréal, Quebec, Canada; and
|| Netherlands Cancer Institute, Amsterdam, The Netherlands
CD4+ T cells control the effector function, memory, and maintenance of CD8+ T cells. Paradoxically, we found that absence of CD4+ T cells enhanced adoptive immunotherapy of cancer when using CD8+ T cells directed against a persisting tumor/self-Ag. However, adoptive transfer of CD4+CD25– Th cells (Th cells) with tumor/self-reactive CD8+ T cells and vaccination into CD4+ T cell-deficient hosts induced autoimmunity and regression of established melanoma. Transfer of CD4+ T cells that contained a mixture of Th and CD4+CD25+ T regulatory cells (Treg cells) or Treg cells alone prevented effective adoptive immunotherapy. Maintenance of CD8+ T cell numbers and function was dependent on Th cells that were capable of IL-2 production because therapy failed when Th cells were derived from IL-2–/– mice. These findings reveal that Th cells can help break tolerance to a persisting self-Ag and treat established tumors through an IL-2-dependent mechanism, but requires simultaneous absence of naturally occurring Treg cells to be effective.
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