CD8⁺ T cell immunity against a tumor/self-antigen is augmented by CD4⁺ T helper cells and hindered by naturally occurring T regulatory cells

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 (T_reg cells) or T_reg 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 T_reg cells to be effective.