Cell therapy with human IL-10-producing ILC2s limits xenogeneic graft-versus-host disease by inhibiting pathogenic T cell responses
Kyle T. Reid,
Sarah J. Colpitts,
Jessica A. Mathews,
Abel Santos Carreira,
Julia M. Murphy,
Dorota T. Borovsky,
Sinthuja Jegatheeswaran,
Wenhui Cui,
Tommy Alfaro Moya,
Nadia Sachewsky,
James An,
Yubing Xia,
Arthur Mortha,
Jong Bok Lee,
Li Zhang,
Igor Novitzky-Basso,
Jonas Mattsson,
Sarah Q. Crome
Affiliations
Kyle T. Reid
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Sarah J. Colpitts
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Jessica A. Mathews
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Abel Santos Carreira
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada
Julia M. Murphy
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Dorota T. Borovsky
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Sinthuja Jegatheeswaran
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Wenhui Cui
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Tommy Alfaro Moya
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada; Postgraduate Medical Education Program, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Nadia Sachewsky
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
James An
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Yubing Xia
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Arthur Mortha
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Jong Bok Lee
Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Li Zhang
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Igor Novitzky-Basso
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada
Jonas Mattsson
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada
Sarah Q. Crome
Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Corresponding author
Summary: 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.
