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Summary: Interleukin-10 (IL-10)-producing group 2 innate lymphoid cells (ILC210) regulate inflammatory immune responses, yet their therapeutic potential remains largely unexplored. Here, we demonstrate that cell therapy with human ILC210 inhibits pathogenic T cell responses in humanized mouse models of graft-versus-host disease (GVHD), resulting in reduced GVHD severity and improved overall survival without limiting the graft-versus-leukemia effect. ILC210 conferred superior protection from GVHD than IL-10−/low ILC2s, and blocking IL-10 and IL-4 abrogated ILC210 protective effects, indicating that these cytokines are important for the protective effects of ILC210. Notably, ILC210 provided comparable protection from GVHD to regulatory T cells without impairing T cell engraftment, instead decreasing intestinal T cell infiltration and suppressing CD4+ Th1 and CD8+ Tc1 cells. CITE-seq of expanded ILC2s revealed CD49d and CD86 are markers that allow for enrichment of ILC210 from conventional ILC2s and tracking of ILC210 in patient studies. Altogether, these findings demonstrate the potential of ILC210 in cell therapies for GVHD and other immune-mediated diseases.

Summary: Natural killer (NK) cell activity is influenced by cytokines and microenvironment factors, resulting in remarkably diverse functions, by contributing to inflammatory responses or serving as rheostats of adaptive immunity. Using single cell RNA sequencing (scRNA-seq), we identified a TGFβ1highCD56brightNK cell population associated with hematopoietic stem cell transplant recipients protected from acute graft-versus-host disease (GVHD). We further define a role for the combination of interleukin-2 (IL-2) and transforming growth factor β1 (TGF-β1) in promoting a regulatory phenotype in NK cells. “Induced” regulatory NK cells produce high amounts of TGF-β1, inhibited T cells, could promote naive T cells differentiation into regulatory T cells, and exhibited a unique transcriptional program that includes expression of IKZF2 (HELIOS) and ZNF683 (HOBIT). This phenotype was not stable, and “induced” regulatory NK cells lost the ability to secrete TGF-β1 upon exposure to different cytokines. These findings define protective CD56brightNK cells post-hematopoietic stem cell transplantation, and demonstrate the combination of IL-2 and TGF-β1 promotes regulatory activity in NK cells.