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Increased Prevalence of Circulating Novel IL-17 Secreting Foxp3 Expressing CD4+ T Cells and Defective Suppressive Function of Circulating Foxp3+ Regulatory Cells Support Plasticity Between Th17 and Regulatory T Cells in Inflammatory Bowel Disease Patients

Ueno, Aito PhD*; Jijon, Humberto MD, PhD*,†; Chan, Ronald MSc*; Ford, Kim BPE*; Hirota, Christina PhD*; Kaplan, Gilaad G. MD, MPh*,†; Beck, Paul L. MD, PhD*,†; Iacucci, Marietta MD; Fort Gasia, Miriam MD*,†; Barkema, Herman W. DVM PhD*; Panaccione, Remo MD*,†; Ghosh, Subrata MD*,†

doi: 10.1097/MIB.0b013e3182a85709
Original Basic Science Articles

Background: IL-17 and Foxp3 double-expressing (DE) CD4+ T lymphocytes are novel crossover immune cell population, but the presence and role of these cells in human intestinal inflammation is unclear. The aim of this study was to investigate the circulating IL-17 and Foxp3 DE CD4+ T lymphocytes in patients with inflammatory bowel disease (IBD).

Methods: The entire cohort consisted of 79 subjects: 31 patients with Crohn's disease, 28 patients with ulcerative colitis, and 20 healthy control subjects (HC). IBD patients with evidence of active disease at endoscopy were entered into the study. Peripheral blood mononuclear cells were used for ex vivo and in vitro studies to assess the characteristics and generation of these novel cells and the function of circulating Foxp3+ CD4+ regulatory T lymphocytes (Treg) in patients with IBD compared with HC.

Results: Patients with IBD had significantly higher prevalence of IL-17 and Foxp3 DE CD4+ T lymphocytes compared with age- and gender-matched HC. These cells expressed RORγt. The ability of Treg cells to suppress autologous T-cell proliferation was reduced by approximately 60% in patients with IBD compared with HC. Increased generation of these DE cells was demonstrated by the modulation of cytokine environment of CD4+ lymphocytes in vitro in patients with Crohn's disease.

Conclusions: Prevalence of circulating IL-17 and Foxp3 DE CD4+ T cells is increased in patients with IBD. Coexpression of RORγt and Foxp3 in these cells implies conversion from Treg cells to Th17 cells. This is associated with a decreased suppressive function of Foxp3+ CD4+ T lymphocytes in patients with IBD.

Article first published online 3 October 2013Supplemental Digital Content is Available in the Text.

*Alberta IBD Consortium, and

Department of Medicine, University of Calgary, Calgary, Alberta, Canada.

Reprints: Aito Ueno, The Alberta IBD Consortium, University of Calgary, 3330 Hospital Drive North West, Calgary, Alberta, Canada T2N1N4 (e-mail:

The Alberta IBD Consortium supported by the Alberta Innovates-Health Solutions.

The authors have no conflicts of interest to disclose.

Supported and funded by the Alberta Inflammatory Bowel Disease Consortium, which is funded by an Alberta Heritage Foundation for Medical Research Interdisciplinary Team Grant (Alberta Heritage Foundation for Medical Research is now Alberta Innovates - Health Solutions).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received July 04, 2013

Accepted August 6, 2013

© Crohn's & Colitis Foundation of America, Inc.
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