Regulatory T cells and inhibitory cytokines in autoimmunity

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Foxp3+ regulatory T cells (Tregs) contribute significantly to the maintenance of peripheral tolerance, but they ultimately fail in autoimmune diseases. The events that lead to Treg failure in controlling autoreactive effector T cells (Teffs) during autoimmunity are not completely understood. In this review, we discuss possible mechanisms for this subversion as they relate to type 1 diabetes (T1D) and multiple sclerosis (MS). Recent studies emphasize firstly, the role of inflammatory cytokines, such as IL-6, in inhibiting or subverting Treg function; secondly, the issue of Treg plasticity; thirdly, the possible resistance of autoimmune T cells to Treg-mediated control; and fourthly, Treg-associated inhibitory cytokines TGFβ, IL-10 and IL-35 in facilitating Treg suppressive activity and promoting Treg generation. These recent advances place a large emphasis on the local tissue specific inflammatory environment as it relates to Treg function and disease development.

Introduction

Autoimmunity ensues when central and/or peripheral tolerance barriers are overcome, thereby allowing the activation of self-reactive T cells, which induce tissue destruction. Most self-reactive T cells are deleted in the thymus, a process referred to as central tolerance. The few remaining self-reactive T cells that enter the periphery are controlled by peripheral tolerance mechanisms, in which Foxp3+ regulatory T cells (Tregs) have emerged as the primary mediators [1]. Autoimmune diseases develop when this last tolerance barrier is compromised. It has been shown that many individuals with no autoimmune manifestations harbor self-reactive T cells [2]. Thus, the continual battle between self-reactive T cells and suppressive Tregs is critical in determining whether autoimmunity commences. Many autoimmune diseases manifest themselves in an oscillating fashion, which is likely because of the aforementioned struggle between the regulatory and inflammatory arms of the immune system, suggesting that Tregs are still actively involved in regulating this self-reactive response. There are three mechanisms that might contribute to a breakdown in Treg control: firstly, Treg numbers are reduced and/or Tregs are dysfunctional because of inherent deficiencies in autoimmune susceptible individuals; secondly, Treg suppressive function is inhibited, diverted or converted by the chronic inflammation that occurs in autoimmunity; and/or thirdly, self-reactive effector T cells (Teff) become unusually aggressive and are refractory to regulation by otherwise functional Tregs because they either overwhelm regulatory control or express molecules that render them resistant. Here, we will discuss how these possibilities might contribute to this loss of Treg control, illustrated by two key autoimmune diseases type 1 diabetes (T1D) and multiple sclerosis (MS), with occasional reference to other autoimmune or inflammatory diseases.

Even though multiple mechanisms of Treg-mediated suppression have been identified, the relative importance of each mechanism in vivo remains unclear [3]. Current dogma, based mostly on in vitro experiments, suggests that Treg function is contact dependent. However, a recent study illustrates that this may be inaccurate as Tregs that are optimally stimulated by contact with Teff can mediate potent third-party suppression via soluble factors in vitro [4••]. These data, together with significant support from in vivo observations, suggest that inhibitory cytokines such as TGFβ, IL-10, and IL-35 are major contributors to Treg function [3, 5]. Consequently, this review will also focus on the contribution of these three inhibitory cytokines in mediating (or failing to mediate) Treg function in autoimmune disease.

Section snippets

Why do Tregs fail to suppress during autoimmune disease?

Under normal conditions, Tregs effectively inhibit excessive inflammation and autoimmune manifestations [6]. However, in autoimmune diseases, Tregs affected by either cell-intrinsic and/or cell–extrinsic factors fail to control the initial inflammatory insult and subsequent disease progression. Studies performed in a variety of autoimmune models suggest that Tregs are still actively and continuously involved in inflammatory regulation after disease onset [7, 8], although this needs to be more

Inhibitory cytokines facilitate Treg-mediated control of Teffs and promote the induction of induced Tregs

As discussed in the previous section, the local inflammatory milieu at the site of autoimmune destruction can have a significant effect on Treg function. Cytokines secreted by Tregs, Teffs and other cellular infiltrates contribute to the generation of this environment. Inhibitory cytokines, such as TGFβ and IL-10, can directly inhibit cells that participate in this autoimmune destruction and/or can mediate the generation of induced T regulatory cells (iTregs) [3]. More recently, IL-35 has also

Concluding remarks

Recent advances have placed significant emphasis on dissecting Treg function in autoimmunity and assessing their therapeutic utility. The local inflammatory environment, consisting of specialized APCs, metabolic components, growth factors and inhibitory and/or inflammatory cytokines, can significantly alter the efficacy and generation of Tregs. Given the complexity of Treg function in vivo, several key questions remain before we fully understand molecular and cellular defects that occur in

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

DAAV is supported by the Juvenile Diabetes Research Foundation International (1-2004-141 [The Robert and Janice Compton Research Grant, In Honor of Elizabeth S. Compton] and 1-2006-847), the NIH (AI072239), the St Jude Cancer Center Support CORE grant (CA-21765) and the American Lebanese Syrian Associated Charities (ALSAC). MB is supported by a Juvenile Diabetes Research Foundation International post-doctoral fellowship (3-2009-594).

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