Enhanced TH17 Responses in Patients with IL10 Receptor Deficiency and Infantile-onset IBD Academic Article uri icon

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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 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.

authors

  • 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 GMS
  • 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

publication date

  • November 2017

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