Synergy of IL-21 and IL-15 in regulating CD8⁺ T cell expansion and function

Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor γ chain [γ_c], which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44^high) and naive (CD44 ^low) phenotype CD8⁺ T cells and augment interferon-γ production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8 ⁺ T cells were impaired in IL-21R^-/- mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8⁺ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8⁺ T cell expansion and effector function, primarily in a synergistic context with IL-15.