Our data demonstrate that IL-13R is functionally expressed by Th17 polarized CD4+ T cells. Th17 cells had a three-fold increase in IL-13Rα1 mRNA expression as quantified by real time PCR compared and IL-13Rα1 expression was seen in Th17 cells and not in naïve (Th0), Th1, or Th2 cells. There was also a greater than 5-fold increase in the mRNA expression of the other component of the IL-13R, IL-4Rα, by real time PCR in Th17 cells compared to Th0, Th1, and Th2 cells. We clearly show that the IL-13R is functional in our system as IL-13 negatively regulates Th17 cell production of IL-17A at the polarization and restimulation stages, and IL-21 production at the Th17 polarization stage. This is in contrast to IL-4 which only downregulated Th17 cytokine production at the polarization phase and not at restimulation, as has also been shown by Harrington and colleagues (1
). We further show that IL-13 decreases the number of IL-17A producing CD4+ cells, but not the amount of IL-17A produced by each cell. IL-13Rα1 expression was only increased on Th17 polarized cells, and not Th1 or Th2 polarized cells. This provides an explanation as to why IL-13 had no effect on cytokine production in Th1 and Th2 polarized T cells, but attenuated Th17 cytokine secretion in Th17 cells. In addition, the presence of IL-13 during Th17 polarization increased the phosphorylation of STAT6 and the mRNA expression of the Th2 transcription factor GATA3 in these cells, which has not been reported in either Th1 or Th2 CD4+ cells.
The IL-13-mediated attenuation of IL-17A production also paralleled a decrease in IL-21 production and ROR-γT relative mRNA expression. ROR-γT is the transcription factor responsible for Th17 proliferation and sustainability (16
) and expression of ROR-γT is increased in the presence of IL-21 (7
). IL-21 and ROR-γT cause an increase in IL-23R expression on the T cells (7
), and IL-23 has shown to be essential in sustaining Th17 cells (7
). Therefore, the observed decreases in IL-17A production could potentially be caused by decreased IL-21 production and ROR-γT expression leading to decreased IL-23R expression on Th17 cells. However, more studies will need to be conducted to confirm this hypothesis.
Although it remains to be formally demonstrated in this article, it seems likely that human Th17 cells will behave similar to mouse Th17 cells. Therefore, since IL-13 inhibits IL-17A production, therapeutic interventions that block IL-13 activity might have unanticipated effects in disease states that are driven by Th17-mediated inflammation. IL-13 has been identified as a potential therapeutic target in allergic diseases, such as asthma, as this cytokine is recognized as a central mediator of mucus production, airway responsiveness, and lymphocyte infiltration in animal models (12
). Molecules that block IL-13 activity, either through antibody neutralization or by soluble receptor, result in reduced airway responsiveness, mucus hyperplasia, inflammation, and chemokine production, such as CCL11, CCL5 and KC, in mice or monkeys (19
). Therefore, based on the results of our study, the use of IL-13 inhibitors in these disease states may have the unintended consequence of upregulating Th17 cytokine production. Increased production of IL-17A could potentially cause induction or exacerbation of autoimmune diseases, such as the EAE model or Crohn’s disease, as mouse models of these diseases are critically dependent on IL-17A (reviewed in (3
)). On the other hand, diseases that cause increases in IL-13 levels might lead to the attenuation of Th17 cytokine production. In this setting, IL-13 mediated downregulation of IL-17A could increase disease severity from extracellular pathogens, such as Klebsiella pneumoniae
) or Mycoplasma pulmonis
), that require IL-17 to resolve the infection.
In summary, we show that Th17 polarized T cells express a functional IL-13R and provide a mechanism by which IL-13, an abundantly produced Th2 cytokine, negatively regulates IL-17A production.