Innate lymphoid cells prevent graft-versus-host disease via IL-9–driven T-cell senescence
Abstract
Abstract 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.
Article Details
Authors (10)
Dejene M. Tufa
Department of Children’s Cancer and Blood Disorders, University of Colorado and Children’s Hospital of Colorado, Aurora, CO
Eric Hoffmeyer
Department of Children’s Cancer and Blood Disorders, University of Colorado and Children’s Hospital of Colorado, Aurora, CO
Kristin L. Schaller
Department of Children’s Cancer and Blood Disorders, University of Colorado and Children’s Hospital of Colorado, Aurora, CO
Ben Kooiman
Department of Children’s Cancer and Blood Disorders, University of Colorado and Children’s Hospital of Colorado, Aurora, CO
Elena Woods
Department of Children’s Cancer and Blood Disorders, University of Colorado and Children’s Hospital of Colorado, Aurora, CO
Dong Wang
Dallas Jones
Department of Children’s Cancer and Blood Disorders, University of Colorado and Children’s Hospital of Colorado, Aurora, CO
Spencer Hall
Department of Children’s Cancer and Blood Disorders, University of Colorado and Children’s Hospital of Colorado, Aurora, CO
Joselyn Cruz Cruz
Department of Children’s Cancer and Blood Disorders, University of Colorado and Children’s Hospital of Colorado, Aurora, CO
Michael R. Verneris
Department of Children’s Cancer and Blood Disorders, University of Colorado and Children’s Hospital of Colorado, Aurora, CO