Mechanisms of allergy and clinical immunology
Human TH17 cells express a functional IL-13 receptor and IL-13 attenuates IL-17A production

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Background

IL-13 is a central mediator of airway responsiveness and mucus expression in patients with allergic airway inflammation, and IL-13 is currently a therapeutic target for asthma. However, little is known about how IL-13 regulates human CD4+ T-cell lineages because IL-13 receptor (IL-13R) α1, a subunit of IL-13R, has not previously been reported to exist on human T cells.

Objective

We sought to determine whether human CD4+ TH17 cells express IL-13Rα1 and whether IL-13 regulates TH17 cytokine production.

Methods

Naive human CD4+ cells were isolated from whole blood, activated with anti-CD3 and anti-CD28, and polarized to TH1, TH2, TH17, or induced regulatory T cells in the presence of IL-13 (0-10 ng/mL). Cell supernatants, total RNA, or total protein was examined 4 days after TH17 polarization.

Results

TH17 cells, but not TH0, TH1, TH2, or induced regulatory T cells, expressed IL-13Rα1. IL-13 attenuated IL-17A production, as well as expression of retinoic acid–related orphan receptor, runt-related transcription factor-1, and interferon regulatory factor 4 in TH17-polarized cells. IL-13 neither inhibited IFN-γ production from TH1 cells nor inhibited IL-4 production from TH2 cells. Furthermore, attenuation of IL-17A production only occurred when IL-13 was present within 24 hours of T-cell activation or at the time of restimulation.

Conclusions

IL-13Rα1 is expressed on human CD4+ TH17 cells, and IL-13 attenuates IL-17A production at polarization and restimulation. Although IL-13 is an attractive therapeutic target for decreasing symptoms associated with asthma, these results suggest that therapies inhibiting IL-13 production could have adverse side effects by increasing IL-17A production.

Section snippets

Isolation of human T cells

All studies were approved by the Institutional Review Board at Vanderbilt University Medical Center. Human PBMCs were isolated from the buffy coats of healthy donors by using Ficoll-Paque Plus (GE Healthcare, Piscataway, NJ). Naive CD4+ T cells were isolated from the PBMCs by using a naive T-cell isolation kit (Miltenyi Biotec, Auburn, Calif). Briefly, CD4+ T cells were negatively selected by incubating mononuclear cells with biotin-labeled antibodies targeting non-CD4+ cells and CD45R0+ memory

Functional IL-13R is expressed on human TH17 cells

Naive human CD4+ T cells were activated with anti-CD3 and anti-CD28 and polarized to become TH1, TH2, TH17, or iTreg cells. Total cellular RNA was collected 4 days after polarization and analyzed for IL-13Rα1 by means of real-time PCR (Fig 1, A). Flow cytometry was conducted and cells were gated on CD3+CD4+ cells to examine surface expression of IL-13Rα1. IL-13Rα1 expression was significantly increased on TH17 cells both as percentages (Fig 1, B) and total numbers of CD3+CD4+IL-13Rα1+ cells (

Discussion

We have previously shown that IL-13Rα1 is expressed on murine TH17 cells and that IL-13 attenuates IL-17A production from TH17 cells.8 In this study we extend these findings to show for the first time that human TH17 cells express IL-13Rα1 and that TH1, TH2, and iTreg cells do not. This is the first report that IL-13Rα1 is expressed in human T cells, likely because TH17 cells were only recently discovered and IL-13Rα1 was not found in other T-cell lineages. We show IL-13Rα1 expression by means

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      The IL-13R is expressed on airway smooth muscle cells, endothelial cells, fibroblasts, bronchial epithelial cells, and most leukocytes, including eosinophils, basophils, mast cells, and B lymphocytes.68–72 It is not expressed on Th1 or Th2 CD4 cells, but is expressed on CD4 Th17 cells.73–75 The interaction between IL-17A and IL-13 is very complex.

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    Supported by the National Institutes of Health (R01 HL 090664, R01 AI 070672, R01 AI 059108, GM 015431, R21 HL106446, R56AI076411 and F32 HL091653), the Department of Veteran Affairs (1I01BX000624), and Vanderbilt Institute for Clinical and Translational Research (VICTR) grant UL1 RR024975.

    Disclosure of potential conflict of interest: G. K. Khurana Hershey and J. K. Kolls have received research support from the National Institutes of Health. R. S. Peebles, Jr, has received research support from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; and the Veterans Administration. The rest of the authors have declared that they have no conflict of interest.

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