Gluten-Dependent Activation of CD4 + T Cells by MHC Class II-Expressing Epithelium.

Autor:	Rahmani S; School of Biomedical Engineering, McMaster University, Hamilton, Ontario, Canada; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Galipeau HJ; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Clarizio AV; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Wang X; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Hann A; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Rueda GH; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Kirtikar UN; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Constante M; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Wulczynski M; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Su HM; Department of Mechanical Engineering, McMaster University, Hamilton, Ontario, Canada., Burchett R; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Bramson JL; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Pinto-Sanchez MI; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Stefanolo JP; C. Bonorino Udaondo Hospital, Buenos Aires, Argentina., Niveloni S; C. Bonorino Udaondo Hospital, Buenos Aires, Argentina., Surette MG; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Murray JA; Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota., Anderson RP; Mackay Base Hospital, Mackay, Queensland, Australia., Bercik P; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Caminero A; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada., Chirdo FG; Instituto de Estudios Inmunológicos y Fisiopatológicos - IIFP (UNLP-CONICET), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina. Electronic address: fchirdo@biol.unlp.edu.ar., F Didar T; School of Biomedical Engineering, McMaster University, Hamilton, Ontario, Canada; Department of Mechanical Engineering, McMaster University, Hamilton, Ontario, Canada. Electronic address: didart@mcmaster.ca., Verdu EF; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: verdue@mcmaster.ca.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2024 Nov; Vol. 167 (6), pp. 1113-1128. Date of Electronic Publication: 2024 Aug 09.
DOI:	10.1053/j.gastro.2024.07.008
Abstrakt:	Background & Aims: Intestinal epithelial cell (IEC) damage is a hallmark of celiac disease (CeD); however, its role in gluten-dependent T-cell activation is unknown. We investigated IEC-gluten-T-cell interactions in organoid monolayers expressing human major histocompatibility complex class II (HLA-DQ2.5), which facilitates gluten antigen recognition by CD4 + T cells in CeD. Methods: Epithelial major histocompatibility complex class II (MHCII) was determined in active and treated CeD, and in nonimmunized and gluten-immunized DR3-DQ2.5 transgenic mice, lacking mouse MHCII molecules. Organoid monolayers from DR3-DQ2.5 mice were treated with or without interferon (IFN)-γ, and MHCII expression was evaluated by flow cytometry. Organoid monolayers and CD4 + T-cell co-cultures were incubated with gluten, predigested, or not by elastase-producing Pseudomonas aeruginosa or its lasB mutant. T-cell function was assessed based on proliferation, expression of activation markers, and cytokine release in the co-culture supernatants. Results: Patients with active CeD and gluten-immunized DR3-DQ2.5 mice demonstrated epithelial MHCII expression. Organoid monolayers derived from gluten-immunized DR3-DQ2.5 mice expressed MHCII, which was upregulated by IFN-γ. In organoid monolayer T-cell co-cultures, gluten increased the proliferation of CD4 + T cells, expression of T-cell activation markers, and the release of interleukin-2, IFN-γ, and interleukin-15 in co-culture supernatants. Gluten metabolized by P aeruginosa, but not the lasB mutant, enhanced CD4 + T-cell proliferation and activation. Conclusions: Gluten antigens are efficiently presented by MHCII-expressing IECs, resulting in the activation of gluten-specific CD4 + T cells, which is enhanced by gluten predigestion with microbial elastase. Therapeutics directed at IECs may offer a novel approach for modulating both adaptive and innate immunity in patients with CeD. (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu