PMID- 32589883 OWN - NLM STAT- MEDLINE DCOM- 20210422 LR - 20220716 IS - 1528-0012 (Electronic) IS - 0016-5085 (Print) IS - 0016-5085 (Linking) VI - 159 IP - 4 DP - 2020 Oct TI - Intestinal Epithelial Expression of MHCII Determines Severity of Chemical, T-Cell-Induced, and Infectious Colitis in Mice. PG - 1342-1356.e6 LID - S0016-5085(20)34853-8 [pii] LID - 10.1053/j.gastro.2020.06.049 [doi] AB - BACKGROUND & AIMS: Intestinal epithelial cells (IECs) provide a barrier that separates the mucosal immune system from the luminal microbiota. IECs constitutively express low levels of major histocompatibility complex (MHC) class II proteins, which are upregulated upon exposure to interferon gamma. We investigated the effects of deleting MHCII proteins specifically in mice with infectious, dextran sodium sulfate (DSS)-, and T-cell-induced colitis. METHODS: We disrupted the histocompatibility 2, class II antigen A, beta 1 gene (H2-Ab1) in IECs of C57BL/6 mice (I-Ab(DeltaIEC)) or Rag1(-/-) mice (Rag1(-/-)I-Ab(DeltaIEC)); we used I-Ab(WT) mice as controls. Colitis was induced by administration of DSS, transfer of CD4(+)CD45RB(hi) T cells, or infection with Citrobacter rodentium. Colon tissues were collected and analyzed by histology, immunofluorescence, xMAP, and reverse-transcription polymerase chain reaction and organoids were generated. Microbiota (total and immunoglobulin [Ig]A-coated) in intestinal samples were analyzed by16S amplicon profiling. IgA(+)CD138(+) plasma cells from Peyer's patches and lamina propria were analyzed by flow cytometry and IgA repertoire was determined by next-generation sequencing. RESULTS: Mice with IEC-specific loss of MHCII (I-Ab(DeltaIEC) mice) developed less severe DSS- or T-cell transfer-induced colitis than control mice. Intestinal tissues from I-Ab(DeltaIEC) mice had a lower proportion of IgA-coated bacteria compared with control mice, and a reduced luminal concentration of secretory IgA (SIgA) following infection with C rodentium. There was no significant difference in the mucosal IgA repertoire of I-Ab(DeltaIEC) vs control mice, but opsonization of cultured C rodentium by SIgA isolated from I-Ab(DeltaIEC) mice was 50% lower than that of SIgA from mAb(WT) mice. Fifty percent of I-Ab(DeltaIEC) mice died after infection with C rodentium, compared with none of the control mice. We observed a transient but significant expansion of the pathogen in the feces of I-Ab(DeltaIEC) mice compared with I-Ab(WT) mice. CONCLUSIONS: In mice with DSS or T-cell-induced colitis, loss of MHCII from IECs reduces but does not eliminate mucosal inflammation. However, in mice with C rodentium-induced colitis, loss of MHCII reduces bacterial clearance by decreasing binding of IgA to commensal and pathogenic bacteria. CI - Copyright (c) 2020 AGA Institute. Published by Elsevier Inc. All rights reserved. FAU - Jamwal, Deepa R AU - Jamwal DR AD - Department of Pediatrics, University of Arizona, Tucson, Arizona. FAU - Laubitz, Daniel AU - Laubitz D AD - Department of Pediatrics, University of Arizona, Tucson, Arizona. FAU - Harrison, Christy A AU - Harrison CA AD - Department of Pediatrics, University of Arizona, Tucson, Arizona. FAU - Figliuolo da Paz, Vanessa AU - Figliuolo da Paz V AD - Department of Pediatrics, University of Arizona, Tucson, Arizona. FAU - Cox, Christopher M AU - Cox CM AD - Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona. FAU - Wong, Rachel AU - Wong R AD - Department of Immunobiology, University of Arizona, Tucson, Arizona. FAU - Midura-Kiela, Monica AU - Midura-Kiela M AD - Department of Pediatrics, University of Arizona, Tucson, Arizona. FAU - Gurney, Michael A AU - Gurney MA AD - Department of Pediatrics, University of Arizona, Tucson, Arizona. FAU - Besselsen, David G AU - Besselsen DG AD - University Animal Care, University of Arizona, Tucson, Arizona. FAU - Setty, Prashanth AU - Setty P AD - Department of Pediatrics, University of Arizona, Tucson, Arizona. FAU - Lybarger, Lonnie AU - Lybarger L AD - Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona. FAU - Bhattacharya, Deepta AU - Bhattacharya D AD - Department of Immunobiology, University of Arizona, Tucson, Arizona. FAU - Wilson, Jean M AU - Wilson JM AD - Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona. FAU - Ghishan, Fayez K AU - Ghishan FK AD - Department of Pediatrics, University of Arizona, Tucson, Arizona. FAU - Kiela, Pawel R AU - Kiela PR AD - Department of Pediatrics, University of Arizona, Tucson, Arizona; Department of Immunobiology, University of Arizona, Tucson, Arizona. Electronic address: pkiela@peds.arizona.edu. LA - eng GR - R01 DK109711/DK/NIDDK NIH HHS/United States GR - R01 DK109701/DK/NIDDK NIH HHS/United States GR - R01 DK119198/DK/NIDDK NIH HHS/United States GR - R01 AI099108/AI/NIAID NIH HHS/United States GR - R01 DK041274/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200623 PL - United States TA - Gastroenterology JT - Gastroenterology JID - 0374630 RN - 0 (Histocompatibility Antigens Class II) SB - IM MH - Animals MH - Colitis/*etiology/metabolism/*pathology MH - Disease Models, Animal MH - Epithelial Cells/*metabolism/*pathology MH - Histocompatibility Antigens Class II/*metabolism MH - Intestinal Mucosa/metabolism/*pathology MH - Mice MH - Mice, Inbred C57BL PMC - PMC9190026 MID - NIHMS1606369 OTO - NOTNLM OT - Activation OT - Antibody Production OT - Antigen Presentation OT - Immune Regulation COIS- Conflict of interest The authors disclose no conflicts. EDAT- 2020/06/27 06:00 MHDA- 2021/04/23 06:00 PMCR- 2022/06/13 CRDT- 2020/06/27 06:00 PHST- 2020/01/24 00:00 [received] PHST- 2020/05/14 00:00 [revised] PHST- 2020/06/10 00:00 [accepted] PHST- 2020/06/27 06:00 [pubmed] PHST- 2021/04/23 06:00 [medline] PHST- 2020/06/27 06:00 [entrez] PHST- 2022/06/13 00:00 [pmc-release] AID - S0016-5085(20)34853-8 [pii] AID - 10.1053/j.gastro.2020.06.049 [doi] PST - ppublish SO - Gastroenterology. 2020 Oct;159(4):1342-1356.e6. doi: 10.1053/j.gastro.2020.06.049. Epub 2020 Jun 23.