Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features

Natural Killer (NK) cells lose their effector functions towards dangerous cells in chronic inflammatory diseases through still elusive mechanisms. Here, we demonstrate that Interleukin 35 (IL-35), an immunosuppressive member of the IL-12 family, inhibits human NK cell proliferation, pro-inflammatory, and cytotoxic functions, while promoting their secretion of TGF-β and proangiogenic factors. Furthermore, prolonged exposure to IL-35 converts NK cells into ILC1-like cells with tissue residency features (CD9 ⁺ CD103 ⁺ CD49a ⁺ ) and low effector functions, that was dependent on autocrine TGF-β. Single cell RNAseq analysis also revealed an ILC1-like heterogeneity associated to the initial NK subpopulation, conventional or adaptive, undergoing the conversion. Overall, our findings identify a new role of IL-35 as a key driver of NK cell plasticity leading to the acquisition of tissue residency features and weakened effector functions that might play a role in physiopathological contexts and represent an attractive target for future immunotherapies to improve NK cell clinical activity.