Cell therapy with human IL-10-producing ILC2s limits xenogeneic graft-versus-host disease by inhibiting pathogenic T cell responses

Interleukin-10 (IL-10)-producing group 2 innate lymphoid cells (ILC2(10)) regulate inflammatory immune responses, yet their therapeutic potential remains largely unexplored. Here, we demonstrate that cell therapy with human ILC2(10) 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. ILC2(10) conferred superior protection from GVHD than IL-10(-/low) ILC2s, and blocking IL-10 and IL-4 abrogated ILC2(10) protective effects, indicating that these cytokines are important for the protective effects of ILC2(10). Notably, ILC2(10) 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 ILC2(10) from conventional ILC2s and tracking of ILC2(10) in patient studies. Altogether, these findings demonstrate the potential of ILC2(10) in cell therapies for GVHD and other immune-mediated diseases.