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

doi:10.1016/j.celrep.2024.115102

Cell therapy with human IL-10-producing ILC2s limits xenogeneic graft-versus-host disease by inhibiting pathogenic T cell responses

Cell Rep. 2024 Dec 24;44(1):115102. doi: 10.1016/j.celrep.2024.115102. Online ahead of print.

Authors

Kyle T Reid¹, Sarah J Colpitts¹, Jessica A Mathews², Abel Santos Carreira³, Julia M Murphy¹, Dorota T Borovsky⁴, Sinthuja Jegatheeswaran¹, Wenhui Cui¹, Tommy Alfaro Moya⁵, Nadia Sachewsky², James An¹, Yubing Xia¹, Arthur Mortha⁴, Jong Bok Lee², Li Zhang⁶, Igor Novitzky-Basso⁷, Jonas Mattsson⁷, Sarah Q Crome⁸

Affiliations

¹ 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.
² Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
⁴ Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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. Electronic address: sarah.crome@utoronto.ca.

PMID: 39721022
DOI: 10.1016/j.celrep.2024.115102

Abstract

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.

Keywords: CP: Immunology; IL-10; ILC2s; Tregs; cell therapy; graft-versus-host disease; graft-versus-leukemic effect; hematopoietic stem cell transplant; immune tolerance; innate lymphoid cells; transplantation.