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 (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.