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

• HSC-derived ILCs produce IL-9 and reduce T cell proliferation.

• Adoptive transfer of HSC-derived ILCs inhibit GVHD in xenogeneic and allogeneic models.

ABSTRACTInnate 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 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 co-culture. Finally, in both human xenogeneic and murine allogeneic hematopoietic cell transplantation (HCT) 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 (GVHD) by inducing T cell senescence.