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Inflamm Bowel Dis. 2017 Nov;23(11):1950-1961. doi: 10.1097/MIB.0000000000001270.

Enhanced TH17 Responses in Patients with IL10 Receptor Deficiency and Infantile-onset IBD.

Author information

1
1Division of Pediatric Gastroenterology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts; 4VEO-IBD Consortium; 5Department of Pediatrics and Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts; 6Harvard Medical School, Boston, Massachusetts; 7Great Ormond Street Hospital London, London, England; 8Translational Gastroenterology Unit, University of Oxford, Oxford, England; 9Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, Gainesville, Florida; 10Division of Gastroenterology and Nutrition, The Children's Hospital at Montefiore, Bronx, New York; 11Pediatric Gastroenterology Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 12Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan; 13Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany; 14Department of Gastroenterology, Children's National Medical Center, Washington, DC; 15Division of Pediatric Hematology and Oncology, University of Michigan, Ann Arbor, Michigan; 16Hospital das Clınicas, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 17Division of Gastroenterology, McMaster Children's Hospital, West Hamilton, Ontario, Canada; 18Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany; 19Division of Pathology, Boston Children's Hospital, Boston, Massachusetts; 20Department of Pediatrics, University of Oxford, Oxford, England; 21Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; 22Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada; 23Department of Biochemistry, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; and 24Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts.

Abstract

BACKGROUND:

IL10 receptor (IL10R) deficiency causes severe infantile-onset inflammatory bowel disease. Intact IL10R-dependent signals have been shown to be important for innate and adaptive immune cell functions in mice. We have previously reported a key role of IL10 in the generation and function of human anti-inflammatory macrophages. Independent of innate immune cell defects, the aim of the current study was to determine the role of IL10R signaling in regulating human CD4 T-cell function.

METHODS:

Peripheral blood mononuclear cells and intestinal biopsies cells were collected from IL10/IL10R-deficient patients and controls. Frequencies of CD4 T-cell subsets, naive T-cell proliferation, regulatory T cell (Treg)-mediated suppression, and Treg and TH17 generation were determined by flow cytometry. Transcriptional profiling was performed by NanoString and quantitative real-time polymerase chain reaction. RNA in situ hybridization was used to determine the quantities of various transcripts in intestinal mucosa.

RESULTS:

Analysis of 16 IL10- and IL10R-deficient patients demonstrated similar frequencies of peripheral blood and intestinal Tregs, compared with control subjects. In addition, in vitro Treg suppression of CD4 T-cell proliferation and generation of Treg were not dependent on IL10R signaling. However, IL10R-deficient T naive cells exhibited higher proliferative capacity, a strong TH17 signature, and an increase in polarization toward TH17 cells, compared with controls. Moreover, the frequency of TH17 cells was increased in the colon and ileum of IL10R-deficient patients. Finally, we show that stimulation of IL10R-deficient Tregs in the presence of IL1β leads to enhanced production of IL17A.

CONCLUSIONS:

IL10R signaling regulates TH17 polarization and T-cell proliferation in humans but is not required for the generation and in vitro suppression of Tregs. Therapies targeting the TH17 axis might be beneficial for IL10- and IL10R-deficient patients as a bridge to allogeneic hematopoietic stem cell transplantation.

PMID:
29023267
DOI:
10.1097/MIB.0000000000001270
[Indexed for MEDLINE]

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