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 T H 17 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 T H 17 signature, and an increase in polarization toward T H 17 cells, compared with controls. Moreover, the frequency of T H 17 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 T H 17 polarization and T-cell proliferation in humans but is not required for the generation and in vitro suppression of Tregs. Therapies targeting the T H 17 axis might be beneficial for IL10- and IL10R-deficient patients as a bridge to allogeneic hematopoietic stem cell transplantation.
Original language | English (US) |
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Pages (from-to) | 1950-1961 |
Number of pages | 12 |
Journal | Inflammatory bowel diseases |
Volume | 23 |
Issue number | 11 |
DOIs | |
State | Published - Nov 1 2017 |
Bibliographical note
Funding Information:D. S. Shouval is a recipient of a Research Fellowship Award Grant from the Crohn’s and Colitis Foundation of America (CCFA) and the Israel Science Foundation (grant 1897/16). L. Konnikova is a recipient of Career Development Award from the CCFA. S. B. Snapper is supported by NIH Grant DK034854, the Helmsley Charitable Trust, and the Wolpow Family Chair in IBD Treatment and Research. D. Kotlarz and C. Klein are supported by the German Research Society (DFG CRC 1054) and the BMBF (German PID-NET). H. H. Uhlig is supported by the Leona M. and Harry B. Helmsley Charitable Trust and by the CCFA. The remaining authors have no conflict of interest to disclose. The authors acknowledge the contribution of the Oxford BRC Gastrointestinal biobank, which is supported by the NIHR Oxford Biomedical Research Centre (11/YH/0020, 16/YH/0247).
Publisher Copyright:
Copyright © 2017 Crohn's & Colitis Foundation.
Keywords
- IL10
- IL10R
- T cells
- TH17
- mucosal homeostasis
- very early-onset-IBD