Generation of Tumor-associated Cytotoxic T Lymphocytes Requires Interleukin 4 from CD8⁺ T Cells

Activation of tumor-associated CD8⁺ cytotoxic T lymphocytes (CTLs) often requires antigen representation, e.g., by dendritic cells (DCs), and CD4⁺ T cell help. Previously, we showed that CTL-mediated tumor immunity required interleukin 4 (IL-4) during the immunization but not effector phase. To determine the source and target cells of IL-4, we performed adoptive T cell transfers using CD4⁺ and CD8⁺ T cells from IL-4^−/− and IL-4R^−/− mice and analyzed CTL generation. Even though necessary for CTL generation, CD4⁺ T cells did not need to express IL-4 or IL-4R. Surprisingly, CTL generation required IL-4 but not IL-4R expression by CD8⁺ T cells. As IL-4 (a) was expressed by naive CD8⁺ T cells within 24 h after antigen encounter, (b) IL-4 induced DC maturation, and (c) CTL development was impaired in T cell–reconstituted IL-4R^−/− mice, CD8⁺ T cell–derived IL-4 appears to act on DCs. We conclude that CD4⁺ and CD8⁺ T cells provide different signals for DC activation during CTL generation.