Innate lymphoid cells prevent graft-versus-host disease via IL-9–driven T-cell senescence

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that regulate tissue homeostasis and immune responses. How ILCs modulate T cells, remains incompletely understood. To investigate the interaction between ILCs and T cells, we differentiated ILC2s and ILC3s from hematopoietic stem cells (HSCs). Both suppressed T-cell proliferation, enhanced cytokine production, and upregulated T-cell senescence-associated surface receptors (CD57, KLRG1, TIGIT, and TIM3). T cells exposed to ILCs also increased expression of senescence-related proteins, including p16, p21, p53, GATA4, and NF-κB. Mechanistically, ILCs produced interleukin-9 (IL-9), and IL-9 blockade prevented ILC-driven T-cell senescence. Conversely, addition of exogenous IL-9 to T cells recapitulated the effects of ILC coculture. Finally, in both human xenogeneic and murine allogeneic hematopoietic cell transplantation models, we observed ILC-mediated T-cell modulation in vivo, with evidence of T-cell senescence. In conclusion, HSC-derived ILCs from both humans and mice mitigate graft-versus-host disease by inducing T-cell senescence.