DOP082 Enhanced TH17 responses in patients with IL10 receptor deficiency and history of infantile-onset IBD

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Abstract

Background: Loss-of-function mutations in the IL10 receptor (IL10R) genes cause severe infantile-onset IBD. Intact IL10R-dependent signals have been shown to be important for innate immune cell function and for regulation of effector and regulatory T cell function in mice. We have previously reported a key role of IL10 is 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 lamina propria cells were extracted from IL10R-deficient patients and controls. Frequencies of CD4+ T cell subsets, naïve T cell proliferation and regulatory T cell (Treg)-mediated suppression and Treg and TH17 generation were determined by flow cytometry. Transcriptional profiling of these populations was performed by quantitative real-time PCR and nanoString platforms.

Results: Analysis of 12 IL10R-deficient patients demonstrated similar frequencies of peripheral blood and colonic lamina propria Tregs, compared to healthy control subjects. Moreover, in vitro Treg suppression of naïve CD4+ T cell proliferation and generation of Treg were not dependent on IL10R signaling. However, IL10R-deficient T naïve cells exhibited significantly higher proliferative capacity, a strong TH17 signature and a marked increase in polarization towards TH17 cells, compared to controls. Moreover, the frequency of TH17 cells was increased in the colon of an IL10R-deficient patient vs. controls.

Conclusions: IL10R signaling regulates TH17 polarization and T cell proliferation in humans, but is not required for the generation of Tregs in blood and mucosal compartments, and is dispensable for in vitro Treg suppression. Therapies targeting the TH17 axis might be beneficial for IL10R-deficient patients as a bridge to hematopoietic stem cell transplantation.

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