Human TH17 cells express a functional IL-13 receptor and IL-13 attenuates IL-17A production

Abstract

Background IL-13 is a central mediator of airway responsiveness and mucus expression in 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 the IL-13 receptor α1 (IL-13Rα1), a subunit of the IL-13 receptor, has not previously been reported to exist on human T cells. Objective To determine if human CD4+ Th17 cells express IL-13Rα1 and if IL-13 regulates Th17 cytokine production. Methods Naïve human CD4+ cells were isolated from whole blood, activated with anti-CD3 and anti-CD28, and polarized to Th1, Th2, Th17, or induced T regulatory cells in the presence of IL-13 (0–10ng/ml). Cell supernatants, total RNA, or total protein was examined four days after Th17 polarization. Results Th17 cells, but not Th0, Th1, Th2 or induced T regulatory cells, expressed IL-13Rα1. IL-13 attenuated IL-17A production as well as expression of RORC2, Runx1, and IRF-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. While 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.

Preclinical Characterization of GLPG0634, a Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases

“…GLPG0634 efficiently blocks cytokine-induced signaling cascades involving JAK1 in several cell lines as well as in human primary cells. Moreover, Th1, Th2, and Th17 differentiation driven by cytokine cocktails, including JAK1-dependent cytokines such as IL-2, IL-4, and IL-6, is also inhibited by GLPG0634 (17,18). These in vitro findings translate to pharmacodynamic readouts in rodents showing that JAK1 signaling is blocked in vivo as measured by a reduction of Mx2 mRNA levels.…”

“…Isolated naive CD4 + T cells were stimulated with plate-bound anti-CD3 (3 mg/ml) and anti-CD28 (5 mg/ml) Abs in the presence of cytokines that drive differentiation into Th1, Th2, or Th17 Th subsets. For Th1 cell polarization, cells were cultured in the presence of 10 mg/ml anti-IL-4 Ab (MAB204; R&D Systems), 10 ng/ml IL-2 (R&D Systems), and 10 ng/ml IL-12 (R&D Systems) (17). For Th2 cell polarization, cells were cultured in the presence of 10 mg/ml anti-IFN-g Ab (Becton Dickinson), 25 ng/ml IL-4 (R&D Systems), and 10 ng/ml IL-2 (17).…”

“…For Th1 cell polarization, cells were cultured in the presence of 10 mg/ml anti-IL-4 Ab (MAB204; R&D Systems), 10 ng/ml IL-2 (R&D Systems), and 10 ng/ml IL-12 (R&D Systems) (17). For Th2 cell polarization, cells were cultured in the presence of 10 mg/ml anti-IFN-g Ab (Becton Dickinson), 25 ng/ml IL-4 (R&D Systems), and 10 ng/ml IL-2 (17). For Th17 cell polarization, a mix of the following cytokines was used: 10 ng/ml IL-6 (R&D Systems), 10 ng/ml IL-1b (R&D Systems), 1 ng/ml TGF-b (PeproTech), and 100 ng/ml IL-23 (R&D Systems) (18).…”

Advances in basic and clinical immunology in 2014

“…One example of the complex interaction of interleukins was provided by Newcomb et al 3 They observed that IL-13 downregulated murine TH17 T cell differentiation and showed that human TH17 T cells expressed IL-13α1, which mediated inhibition of IL17A production. The authors suggested that strategies targeting IL-13 effects for asthma and allergic diseases might increase TH17 responses.…”

The Type I and Type II Receptor Complexes for IL-4 and IL-13 Differentially Regulate Allergic Lung Inflammation

“…It is through this Type II receptor complex that IL-4 and IL-13 mediate their effects on non-hematopoietic cells, which generally lack C, and therefore Type I receptor expression. IL-13R1 surface expression is absent on resting mouse and human T-cells and on mouse B-cells (Ogata, et al, 1998, Umeshita-Suyama, et al, 2000, although recent studies suggested inducible expression on mouse and human CD4+ T-cells (Newcomb, et al, 2009, Newcomb, et al, 2011. Related evolutionarily to C, IL-13R1 has acquired a third extra Ig-like domain, D1, allowing extra contacts with IL-13 in Type II receptor complexes (LaPorte, et al, 2008).…”