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Shouval, Dror S.; Konnikova, Liza; Griffith, Alexandra E.; Wall, Sarah M.; Biswas, Amlan; Werner, Lael; Nunberg, Moran; Kammermeier, Jochen; Goettel, Jeremy A.; Anand, Rajsavi; Chen, Hannah; Weiss, Batia; Li, Jian; Loizides, Anthony; Yerushalmi, Baruch; Yanagi, Tadahiro; Beier, Rita; Conklin, Laurie S.; Ebens, Christen L.; Santos, Fernanda G. M. S.; Sherlock, Mary; Goldsmith, Jeffery D.; Kotlarz, Daniel; Glover, Sarah C.; Shah, Neil; Bousvaros, Athos; Uhlig, Holm H.; Muise, Aleixo M.; Klein, Christoph; Snapper, Scott B. (2017): Enhanced T(H)17 Responses in Patients with IL10 Receptor Deficiency and Infantile-onset IBD. In: Inflammatory Bowel Diseases, Vol. 23, No. 11: pp. 1950-1961
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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 IL1b 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.