<i>Enterococcus faecalis</i> induces MHC-II expression by the intestinal epithelium during murine graft-versus-host disease
Abstract
Abstract Intestinal Enterococcus domination has been associated with an increased risk of mortality from acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), a curative-intent treatment for patients with hematologic malignancies. In this study, we investigated interactions between Enterococcus and the intestinal epithelium as a mechanism to aggravate GVHD. We observed that endogenous intestinal Enterococcus outgrowth was associated with increased GVHD mortality and major histocompatibility complex class II (MHC-II) expression by intestinal epithelial cells in the colon in an MHC-disparate mouse model of GVHD. Monocolonization of nontransplanted gnotobiotic mice with Enterococcus faecalis was sufficient to induce colonic MHC-II expression. Conversely, select species within the genus Enterococcus, as well as a consortium of 4 anaerobic commensal bacteria including Blautia producta, did not affect colonic MHC-II expression in gnotobiotic mice. In addition, E faecalis colonization induced inflammatory responses in CD4+ T cells and natural killer cells from the colonic lamina propria, the 2 main sources of interferon gamma production that drives MHC-II expression in nonprofessional antigen-presenting cells. We further explored the potential therapeutic benefit of establishing colonization resistance against E faecalis through administration of a lantibiotic-producing B producta strain after allo-HCT. Colonization of transplanted mice with a consortium of commensal bacteria containing the lantibiotic-producing B producta strain prevented intestinal Enterococcus domination after transplantation and improved GVHD survival. Our results demonstrate a potential mechanism by which Enterococcus aggravates GVHD through increased MHC-II expression in the intestinal epithelium. Targeting the Enterococcus–epithelium–MHC-II axis thus presents a therapeutic opportunity to prevent lethal GVHD.
Article Details
Authors (22)
Chi L. Nguyen
1Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Jennifer Funes
2Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
Romina Ghale
1Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Nathan Duong
2Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
Kristen Victor
1Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Brianna Gipson
Zhenrun J. Zhang
3Biological Sciences Division, Duchossois Family Institute, University of Chicago, Chicago, IL
Anqi Dai
Rita Li
2Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
Gabriel Armijo
1Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Ashley Huang
2Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
Miriam Martinez
2Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
Yuqing Chen
Zhejiang Engineering Laboratory for Green Syntheses and Applications of Fluorine-Containing Specialty Chemicals, Institute of Advanced Fluorine-Containing Materials
Daniel Ghazarian
2Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
Melissa Docampo
1Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Khyatiben Pathak
4Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA
Patrick Pirrotte
Kate A. Markey
5Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
Jonathan U. Peled
7Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Jenny Paredes
2Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
Marina Burgos da Silva
1Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
Marcel R. M. van den Brink