HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44(+) Natural Killer Cells  in Ulcerative Colitis.

HLA-DP Antigens; Humans; HLA-DP Antigens/genetics; Colitis, Ulcerative/genetics; Killer Cells, Natural; Haplotypes; Epithelial Cells; HLA-DP; Intestinal Organoids; NK Cells; NKp44; Ulcerative Colitis

Abstract :

[en] BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms 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. METHODS: 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 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. RESULTS: 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 with controls. IECs in human intestinal 3D organoids derived from HLA-DP401(pos) individuals showed significantly stronger binding of NKp44 compared with HLA-DP301(pos) IECs. HLA-DP401(pos) IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44(+) NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301(pos) organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. CONCLUSIONS: We identified 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.

Disciplines :

Gastroenterology & hepatology

Author, co-author :

Baumdick, Martin E; Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

Niehrs, Annika; Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

Degenhardt, Frauke; Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.

Schwerk, Maria; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Hinrichs, Ole; Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

Jordan-Paiz, Ana; Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

Padoan, Benedetta; Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

Wegner, Lucy H M; Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

Schloer, Sebastian; 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 Münster, Münster, Germany.

Zecher, Britta F; Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

More authors (24 more)

Other collaborator :

Akar, Alaa

Flemming, Cornelius

Felix

Flomm

Flosbach, Markus

Jäger, Julia

Jeromin, Niklas

Jung, Johannes

Ohms, Mareike

Reinshagen, Konrad

More authors (224 more)

Language :

English

Title :

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44(+) Natural Killer Cells in Ulcerative Colitis.

Publication date :

October 2023

Journal title :

Gastroenterology

ISSN :

0016-5085

eISSN :

1528-0012

Publisher :

Elsevier

Volume :

165

Issue :

Pages :

946-962.e13

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.gastrojournal.org

European Projects :

H2020 - 884830 - RegNK - Regulation of NK cell function

Funders :

EU - European Union

Funding number :

75N91019D00024/CA/NCI NIH HHS/United States

Funding text :

This work was supported by the Daisy Huet Roell Foundation, the European Research Council (ERC) (EU Horizon 2020, #884830), the Landesforschungsförderung (LFF-75) Hamburg City of Hamburg, the DFG (CRC/1192), the DFG (SFB1328), the BMBF (eMed Consortia Fibromap), and the Novo Nordisk Foundation (Young Investigator Award – NNF21OC0066381). This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E, and by the Intramural Research Program of the National Institutes of Health, Frederick National Laboratory, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The Leibniz Institute of Virology is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health.

Commentary :

Available on ORBi :

since 17 December 2023

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