Human Natural Killer Cells Licensed by KIR Genes Have an Altered Cytokine Program That Modifies CD4+ T Cell Function

摘要

Natural killer (NK) cells are innate immune cells known for their cytolytic activities towards tumors and infections. They are capable of expressing diverse killer immunoglobulin receptors (KIRs), and KIRs are implicated in susceptibility to Crohn’s disease (CD), a chronic intestinal inflammatory disease. However, the cellular mechanism of this genetic contribution is unknown. Here we show that the ‘licensing’ of NK cells, determined by the presence of KIR2DL3 and homozygous HLA-C1 in host genome, results in their cytokine reprogramming, which permits them to promote CD4⁺ T cell activation and TH17 differentiation ex vivo. Microfluidic analysis of thousands of NK single cells and bulk secretions established that licensed NK cells are more polarized to pro-inflammatory cytokine production than unlicensed NK cells, including production of IFN-γ, TNF-α, CCL-5, and macrophage inflammatory protein (MIP)-1β. Cytokines produced by licensed NK augmented CD4⁺ T cell proliferation and IL-17A/IL-22 production. Antibody blocking indicated a primary role for IFN-γ, TNF-α, and IL-6 in the augmented T cell proliferative response. In conclusion, NK licensing mediated by KIR2DL2/3 and HLA-C1 elicits a novel NK cytokine program that activates and induces pro-inflammatory CD4⁺ T cells, thereby providing a potential biologic mechanism for KIR-associated susceptibility to CD and other chronic inflammatory diseases.