TY - JOUR
T1 - HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis
AU - Baumdick, Martin E.
AU - Niehrs, Annika
AU - Degenhardt, Frauke
AU - International Inflammatory Bowel Disease Genetics Consortium
AU - Schwerk, Maria
AU - Hinrichs, Ole
AU - Jordan-Paiz, Ana
AU - Padoan, Benedetta
AU - Wegner, Lucy H. M.
AU - Schloer, Sebastian
AU - Zecher, Britta F.
AU - Malsy, Jakob
AU - Joshi, Vinita R.
AU - Illig, Christin
AU - Schröder-Schwarz, Jennifer
AU - Möller, Kimberly J.
AU - Hamburg Intestinal Tissue Study Group
AU - Akar, Alaa
AU - Flemming, Cornelius
AU - Felix, null
AU - Flomm, null
AU - Flosbach, Markus
AU - Jäger, Julia
AU - Jeromin, Niklas
AU - Jung, Johannes
AU - Ohms, Mareike
AU - Reinshagen, Konrad
AU - Rische, Johann
AU - Sagebiel, Adrian
AU - Sandfort, Deborah
AU - Steinert, Fenja
AU - Tomuschat, Christian
AU - Wesche, Jasmin
AU - Martin, Maureen P.
AU - Yuki, Yuko
AU - Ozawa, Mikki
AU - Sauter, J. rgen
AU - Schmidt, Alexander H.
AU - Perez, Daniel
AU - Giannou, Anastasios D.
AU - Carrington, Mary
AU - Davis, Randall S.
AU - Schumacher, Udo
AU - Sauter, Guido
AU - Huber, Samuel
AU - Puelles, Victor G.
AU - Melling, Nathaniel
AU - Franke, Andre
AU - Shifteh Abedian, null
AU - van Limbergen, Johan
AU - Ponsioen, Cyriel Y.
AU - Bunders, Madeleine J.
N1 - Funding Information: Funding 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. Funding Information: Funding 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 . Publisher Copyright: © 2023 The Authors
PY - 2023/10/1
Y1 - 2023/10/1
N2 - 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-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos 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-DP301pos 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.
AB - 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-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos 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-DP301pos 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.
KW - HLA-DP
KW - Intestinal Organoids
KW - NK Cells
KW - NKp44
KW - Ulcerative Colitis
UR - http://www.scopus.com/inward/record.url?scp=85170657087&partnerID=8YFLogxK
U2 - https://doi.org/10.1053/j.gastro.2023.06.034
DO - https://doi.org/10.1053/j.gastro.2023.06.034
M3 - Article
C2 - 37454979
SN - 0016-5085
VL - 165
SP - 946-962.e13
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -