Publication
Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates.
Journal Paper/Review - Jun 28, 2023
Tkachev Victor, Vanderbeck Ashley, Perkey Eric, Furlan Scott N, McGuckin Connor, Gómez Atria Daniela, Gerdemann Ulrike, Rui Xianliang, Lane Jennifer, Hunt Daniel J, Zheng Hengqi, Colonna Lucrezia, Hoffman Michelle, Yu Alison, Outen Riley, Kelly Samantha, Allman Anneka, Koch Ute, Radtke Freddy, Ludewig Burkhard, Burbach Brandon, Shimizu Yoji, Panoskaltsis-Mortari Angela, Chen Guoying, Carpenter Stephen M, Harari Olivier, Kuhnert Frank, Thurston Gavin, Blazar Bruce R, Kean Leslie S, Maillard Ivan
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Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch's effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4β7 in conventional T cells while preserving α4β7 in regulatory T cells, with findings suggesting increased β1 competition for α4 binding in conventional T cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4β7 integrin in T cells after allo-HCT. Together, DLL4-Notch blockade decreased effector T cell infiltration into the gut, with increased regulatory to conventional T cell ratios early after allo-HCT. Our results identify a conserved, biologically unique, and targetable role of DLL4-Notch signaling in intestinal GVHD.