Cell therapy with IL-10-producing group 2 innate lymphoid cells suppresses Graft-versus-Host disease

Abstract IL-10 producing group 2 innate lymphoid cells (ILC2 10 ) have immunoregulatory functions, and limit harmful immune responses across various tissues. Despite their crucial roles in maintaining immune homeostasis, the cell therapy potential of human ILC2 10 has not been demonstrated, due to both limited numbers in human peripheral blood and lack of definitive markers for identification. Here, we isolate and expand circulating human ILC2 10 , and assess their cell therapy potential in a humanized model of Graft-versus-Host Disease (GVHD). Cell therapy with human ILC2 10 decreased GVHD severity and prolonged survival of NOD- scid IL2Rγ null (NSG) mice. Adoptive transfer of ILC2 10 inhibited pathogenic T cell proliferation and intestinal infiltration, and suppressed CD4 + Th1 and CD8 + Tc1 cells in an IL-4 and IL-10 dependent manner. Critically, increased proportions of ILC2s did not correlate with higher rates of cancer relapse in HSCT recipients, and adoptive transfer of ILC2 10 did not compromise graft-versus-leukemic (GVL) effects in a humanized model. Finally, we identify CD49d and CD86 as novel markers that discriminate ILC2 10 from conventional ILC2s. Collectively, these findings demonstrate the potential of harnessing ILC2 10 in cell therapies for GVHD and other immune-driven pathologies.