Expression and function of TNF and IL-1 receptors on human regulatory T cells.

Frances Mercer,Derya Unutmaz,Lina Kozhaya

doi:10.1371/journal.pone.0008639

Abstract

Regulatory T cells (Tregs) suppress immune activation and are critical in preventing autoimmune diseases. While the ability of Tregs to inhibit proliferation of other T cells is well established, it is not yet clear whether Tregs also modulate inflammatory cytokines during an immune response. Here, we show that the expression of inflammatory cytokine receptors IL-1R1 and TNFR2 were higher on resting mature Tregs compared to naïve or memory T cells. While upon activation through the T cell receptor (TCR), expression of IL-1R1 and TNFR2 were upregulated on all T cell subsets, IL-1R1 maintained significantly higher expression on activated Tregs as compared to other T cell subsets. The decoy receptor for IL-1 (IL-1R2) was not expressed by any of the resting T cells but was rapidly upregulated and preferentially expressed upon TCR-stimulation on Tregs. In addition, we found that Tregs also expressed high levels of mRNA for IL-1 antagonist, IL-1RA. TCR-stimulation of naïve T cells in the presence of TGFβ, which induces FOXP3 expression, however did not result in upregulation of IL-1R1 or IL-1R2. In addition, ectopic expression of FOXP3 in non-Tregs, while causing significant upregulation of IL-1R1 and IL-1R2, did not achieve the levels seen in bona fide Tregs. We also determined that resting human Tregs expressing IL-1R1 did not have higher suppressive capacity compared to IL-1R1- Tregs, suggesting that IL-1R1 does not discriminate suppressive resting Tregs in healthy individuals. Functionally, activated human Tregs displayed a capacity to neutralize IL-1β, which suggests a physiological significance for the expression of IL-1 decoy receptor on Tregs. In conclusion, our findings that human Tregs preferentially express receptors for TNF and IL-1 suggest a potential function in sensing and dampening local inflammation.

Highlights

Regulatory T cells (Treg) are characterized by the ability to suppress immune activation [1]
In order to identify new effector molecules that may contribute to Treg function, we had performed differential gene expression analysis of CD4+ cells subsets, which were isolated based on expression of CD25 and CD45RO: Naıve, (TN defined as CD25CD45RO2), Memory, (TM defined as CD252CD45RO+), Naıve Treg, (TNreg defined as CD25+CD45RO2), and Treg (CD25+CD45RO+) as described [14]
During the course of analysis of this data set we found that several cytokine receptors, IL-1R1, IL-1R2 and TNFR2, which were recently reported to be preferentially expressed on human and murine Tregs [6,15] or in vitro expanded human Tregs [5] were preferentially expressed on resting or activated ex vivo human Tregs

Summary

Introduction

Regulatory T cells (Treg) are characterized by the ability to suppress immune activation [1]. Tregs are a subset of CD4+ cells and are typically identified based on CD25 and FOXP3 expression [1]. The latter is a transcription factor necessary for their development and function [1]. While it is well established that Tregs are highly potent in inhibiting the activation and proliferation of other T cell subsets in vitro and in vivo, the exact mechanisms of this suppression are not fully understood [2].

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Conclusion