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

Overview

Journal Gastroenterology

Specialty Gastroenterology

Date 2023 Jul 16

PMID 37454979

Authors

Martin E Baumdick

Annika Niehrs

Frauke Degenhardt

Maria Schwerk

Ole Hinrichs

Ana Jordan-Paiz

Benedetta Padoan

Lucy H M Wegner

Sebastian Schloer

Britta F Zecher

Jakob Malsy

Vinita R Joshi

Christin Illig

Jennifer Schroder-Schwarz

Kimberly J Moller

Maureen P Martin

Yuko Yuki

Mikki Ozawa

Jurgen Sauter

Alexander H Schmidt

Daniel Perez

Anastasios D Giannou

Mary Carrington

Randall S Davis

Udo Schumacher

Guido Sauter

Samuel Huber

Victor G Puelles

Nathaniel Melling

Andre Franke

Marcus Altfeld

Madeleine J Bunders

Affiliations

Soon will be listed here.

Abstract

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 individuals showed significantly stronger binding of NKp44 compared with HLA-DP301 IECs. HLA-DP401 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 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.

Citing Articles

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