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

• DOI: 10.1053/j.gastro.2023.06.034
• Publication Date: 2023-07-15T00:56:12Z
• 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 Schröder...; Kimberly J. Möller; Alaa Akar; Cornelius Flemming; Felix; Flomm; Markus Flosbach; Julia Jäger; Niklas Jeromin; Johannes Jung; Mareike Ohms; Konrad Reinshagen; Johann Rische; Adrian Sagebiel; Deborah Sandfort; Fenja Steinert; Christian Tomuschat; Jasmin Wesche; Maureen P. Martin; Yuko Yuki; Mikki Ozawa; Jürgen Sauter; Alexander H. Schmidt; Daniel Perez; Anastasios D. Gia...; Mary Carrington; Randall S. Davis; Udo Schumacher; Guido Sauter; Samuel Huber; Victor G. Puelles; Nathaniel Melling; Andre Franke; Shifteh Abedian; Clara Abraham; Jean-Paul Achkar; Tariq Ahmad; Rudi Alberts; Behrooz Alizadeh; Leila Amininejad; Ashwin N. Anantha...; Vibeke Andersen; Carl A. Anderson; Jane M. Andrews; Vito Annese; Guy Aumais; Leonard Baidoo; Robert N. Baldassano; Peter A. Bampton; Murray Barclay; Jeffrey C. Barrett; Johannes Bethge; Claire Bewshea; Joshua C. Bis; Alain Bitton; Thelma BK; Gabrielle Boucher; Oliver Brain; Stephan Brand; Steven R. Brant; Jae Hee Cheon; Angela Chew; Judy H. Cho; Isabelle Cleynen; Ariella Cohain; Rachel Cooney; Anthony Croft; Mark J. Daly; Mauro D'Amato; Silvio Danese; Naser Ebrahim Dar...; Lisa Wu Datta; Frauke Degenhardt; Goda Denapiene; Lee A. Denson; Kathy L. Devaney; Olivier Dewit; Renata D'Inca; Hazel E. Drummond; Marla Dubinsky; Richard H. Duerr; Cathryn Edwards; David Ellinghaus; Pierre Ellul; Motohiro Esaki; Jonah Essers; Lynnette R. Ferguson; Eleonora A. Festen; Philip Fleshner; Tim Florin; Denis Franchimont; Andre Franke; Yuta Fuyuno; Richard Gearry; Michel Georges; Christian Gieger; Jürgen Glas; Philippe Goyette; Todd Green; Anne M. Griffiths; Stephen L. Guthery; Hakon Hakonarson; Jonas Halfvarson; Katherine Hanigan; Talin Haritunians; Ailsa Hart; Chris Hawkey; Nicholas K. Hayward; Matija Hedl; Paul Henderson; Georgina L. Hold; Myhunghee Hong; Xinli Hu; Hailiang Huang; Jean-Pierre Hugot; Ken Y. Hui; Marcin Imielinski; Omid Jazayeri; Laimas Jonaitis; Luke Jostins; Garima Juyal; Ramesh Chandra Juyal; Rahul Kalla; Tom H. Karlsen; Nicholas A. Kennedy; Mohammed Azam Khan; Won Ho Kim; Takanari Kitazono; Gediminas Kiudelis; Michiaki Kubo; Subra Kugathasan; Limas Kupcinskas; Christopher A. Lamb; Katrina M. de Lange; Anna Latiano; Debby Laukens; Ian C. Lawrance; James C. Lee; Charlie W. Lees; Marcis Leja; Nina Lewis; Johan Van Limbergen; Paolo Lionetti; Jimmy Z. Liu; Edouard Louis; Yang Luo; Gillian Mahy; Masoud Mohammad M...; Reza Malekzadeh; John Mansfield; Suzie Marriott; Dunecan Massey; Christopher G. Ma...; Toshiyuki Matsui; Dermot P.B. McGovern; Andrea van der Me...; Vandana Midha; Raquel Milgrom; Samaneh Mirzaei; Mitja Mitrovic; Grant W. Montgomery; Craig Mowat; Christoph Müller; William G. Newman; Aylwin Ng; Siew C. Ng; Sok Meng Evelyn Ng; Susanna Nikolaus; Kaida Ning; Markus Nöthen; Ioannis Oikonomou; David Okou; Timothy R. Orchard; Orazio Palmieri; Miles Parkes; Anne Phillips; Cyriel Y. Ponsioen; Urõs Potocnik; Hossein Poustchi; Natalie J. Prescott; Deborah D. Proctor; Graham Radford-Smith; Jean- Francois Ra...; Miguel Regueiro; Walter Reinisch; Florian Rieder; John D. Rioux; Rebecca Roberts; Gerhard Rogler; Richard K. Russell; Jeremy D. Sanderson; Miquel Sans; Jack Satsangi; Eric E. Schadt; Michael Scharl; John Schembri; Stefan Schreiber; L. Philip Schumm; Regan Scott; Mark Seielstad; Tejas Shah; Yashoda Sharma; Mark S. Silverberg; Alison Simmons; Lisa A. Simms; Abhey Singh; Jurgita Skiecevic...; Suzanne van Sommeren; Kyuyoung Song; Ajit Sood; Sarah L. Spain; A. Hillary Steinhart; Joanne M. Stempak; Laura Stronati; Joseph J.Y. Sung; Stephan R. Targan; Kirstin M. Taylor; Emilie Theatre; Leif Torkvist; Esther A. Torres; Mark Tremelling; Holm H. Uhlig; Junji Umeno; Homayon Vahedi; Eric Vasiliauskas; Anje ter Velde; Nicholas T. Ventham; Severine Vermeire; Hein W. Verspaget; Martine De Vos; Thomas Walters; Kai Wang; Ming-Hsi Wang; Rinse K. Weersma; Zhi Wei; David Whiteman; Cisca Wijmenga; David C. Wilson; Juliane Winkelmann; Sunny H. Wong; Ramnik J. Xavier; Keiko Yamazaki; Suk-Kyun Yang; Byong Duk Ye; Sebastian Zeissig; Bin Zhang; Clarence K. Zhang; Hu Zhang; Wei Zhang; Hongyu Zhao; Zhen Z. Zhao; Marcus Altfeld; Madeleine J. Bunders
• Keywords: HLA-DP Antigens; Hepatology; HLA-DP; Gastroenterology; Biology and Life Sciences; Ulcerative; Epithelial Cells; Colitis; NK Cells; 3. Good health; Killer Cells, Natural; Haplotypes; Medicine and Health Sciences; Natural; NKp44; Killer Cells; Ulcerative Colitis; Humans; Colitis, Ulcerative; Intestinal Organoids; Intes-tinal Organoids

Background & AimsUlcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, associated with specific risk single nucleotide polymorphisms in HLA class II. Given recently discovered interactions between subsets HLA-DP molecules activating natural killer (NK) cell receptor NKp44, genetic associations UC haplotypes their functional implications were investigated.MethodsHLA-DP haplotype association analyses performed (UC: n = 13,927; control: 26,764). Expression levels on epithelial cells (IECs) individuals without quantified. Human 3-dimensional (3D) organoid cocultures human NK used to determine consequences NKp44.ResultsThese studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) protective for European populations. expression was significantly higher IECs compared controls. 3D organoids derived from HLA-DP401pos showed stronger binding NKp44 HLA-DP301pos IECs. triggered increased degranulation tumor necrosis factor production NKp44+ cocultures, resulting enhanced death organoids. Blocking HLA-DP401–NKp44 (anti-NKp44) abrogated activity cocultures.ConclusionsWe an that engages activates cells, mediating damage haplotype–dependent manner. The molecular interaction HLA-DP401 can be targeted therapeutic interventions reduce cell–mediated epithelium UC. Ulcerative investigated. NKp44. These cocultures. We