IL-15 as a mediator of CD4⁺ help for CD8⁺ T cell longevity and avoidance of TRAIL-mediated apoptosis

CD4⁺ helper T cells contribute to the induction and maintenance of antigen-specific CD8⁺ T cells. Their absence results in short-lived antigen-specific CD8⁺ T cells and defective secondary CD8⁺ T cell responses because of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Here, we show that IL-15 codelivered with vaccines can overcome CD4⁺ T cell deficiency for promoting longevity of antigen-specific CD8⁺ T cells and avoidance of TRAIL-mediated apoptosis. In both priming and secondary responses, IL-15 down-regulates proapoptotic Bax, an intermediate in TRAIL-mediated apoptosis, and increases anti-apoptotic Bcl-X_L in CD8⁺ T cells. Thus, IL-15 is sufficient to mimic CD4⁺ T cell help. Antigen-specific CD4⁺ T cells induce dendritic cells (DCs) to produce IL-15. IL-15 is also necessary for optimal help, because helper cells do not deliver effective help through IL-15^-/- DCs. Therefore, IL-15 codelivered with vaccines can overcome CD4⁺ helper T cell deficiency for induction of functionally efficient CD8⁺ T cells and maintenance of CD8 ⁺ cytotoxic T lymphocytes (CTLs), and IL-15 is probably one of the natural mediators of help. These findings suggest new vaccine strategies against infections and cancers, especially in individuals with CD4-deficiency.