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HLA-DP on Epithelial Cells enables Tissue Damage by NKp44+ NK Cells in Ulcerative Colitis

  1. Author:
    Baumdick, Martin E
    Niehrs, Annika
    Degenhardt, Frauke
    Schwerk, Maria
    Hinrichs, Ole
    Jordan-Paiz, Ana
    Padoan, Benedetta
    Wegner, Lucy H M
    Schloer, Sebastian
    Zecher, Britta F
    Malsy, Jakob
    Joshi, Vinita R
    Illig, Christin
    Schröder-Schwarz, Jennifer
    Möller, Kimberly J
    Martin,Pat
    Yuki,Yuko
    Ozawa, Mikki
    Sauter, Jürgen
    Schmidt, Alexander H
    Perez, Daniel
    Giannou, Anastasios D
    Carrington, Mary
    Davis, Randall S
    Schumacher, Udo
    Sauter, Guido
    Huber, Samuel
    Puelles, Victor G
    Melling, Nathaniel
    Franke, Andre
    Altfeld, Marcus
    Bunders, Madeleine J

  2. Author Address

    Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany., Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany; Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and "Cells in Motion" Interfaculty Center, University of M 252;nster, M 252;nster, Germany., Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany; I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany; I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-L 252;beck-Borstel-Riems, Germany., Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., One Lambda, Inc., Canoga Park, CA, USA., DKMS, T 252;bingen, Germany., DKMS, T 252;bingen, Germany; DKMS Life Science Lab, Dresden, Germany., Department of General, Visceral and Thoraic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Department of General, Visceral and Thoraic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA., Departments of Medicine, Microbiology, and Biochemistry & Molecular Genetics, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark., Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: madeleine.bunders@leibniz-liv.de.,
    1. Year: 2023
    2. Date: Oct
    3. Epub Date: 2023 07 14
  2. Journal: Gastroenterology
    1. 165
    2. 4
    3. Pages: 946-962.e13.
  4. Type of Article: Article
  1. Abstract:

    Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and associated with risk single nucleotide polymorphism in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. HLA-DP haplotype and UC risk association analyses were performed (UC: N= 13,927; control: N= 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3D-organoid co-cultures with human NK cells were employed to determine functional consequences of interactions between HLA-DP and NKp44. These studies identified HLA-DPA1*01:03-DPB1*04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1*01:03-DPB1*03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared to controls. IECs in human intestinal 3D-organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared to HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and TNF production by NKp44+ NK cells in co-cultures, resulting in enhanced epithelial cell death compared to HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in co-cultures. Here, we identify an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC. Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.

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  2. DOI: 10.1053/j.gastro.2023.06.034
  3. PMID: 37454979
  4. PMCID: PMC10529779
  5. PII : S0016-5085(23)04772-8

Library Notes

  1. Fiscal Year: FY2023-2024
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