IL-21-induced MHC class II+ NK cells promote the expansion of human uncommitted CD4⁺ central memory T cells in a macrophage migration inhibitory factor-dependent manner

NK cells are critical for innate immunity-mediated protection. The main roles of NK cells rely on their cytotoxic functions or depend on the tuning of Th1 adaptive immunity by IFN-g. However, the precise influence of inflammatory cytokines on NK cell and CD4 T lymphocyte interactions was never investigated. In this study, we provide evidence that IL-21, a cytokine produced during chronic inflammation or infectious diseases, promotes the differentiation of a specific subset of NK cells coexpressing CD86 and HLA-DR and lacking NKp44. More importantly, IL-21-propagated HLA-DR+ NK cells produce macrophage migration inhibitory factor and provide costimulatory signaling during naive CD4⁺ T cell priming inducing the differentiation of uncommitted central memory T cells. Central memory T cells expanded in the presence of HLA-DR+ NK cells are CXCR3⁺CCR62 CCR42CXCR52 and produce IL-2, as well as low levels of TNF-a. Costimulation of CD4⁺ T cells by HLA-DR+ NK cells prevents the acquisition of effector memory phenotype induced by IL-2. Moreover, we identified this population of NK HLA-DR+ macrophage migration inhibitory factor+ cells in inflammatory human appendix. Collectively, these results demonstrate a novel function for IL-21 in tuning NK and CD4⁺ T cell interactions promoting a specific expansion of central memory lymphocytes.