Elsevier

Seminars in Immunology

Volume 25, Issue 4, 15 November 2013, Pages 305-312
Seminars in Immunology

Review
The plasticity of human Treg and Th17 cells and its role in autoimmunity

https://doi.org/10.1016/j.smim.2013.10.009Get rights and content

Highlights

  • Human CD4+ T cells can display a high grade of plasticity.

  • Th17 cells can adapt Th1- and Th2-type phenotypes.

  • FoxP3+ Tregs can differentiate into Th1- and Th17-like cells.

  • These mechanisms may play a role in autoimmune diseases like MS.

Abstract

CD4+ T helper cells are a central element of the adaptive immune system. They protect the organism against a wide range of pathogens and are able to initiate and control many immune reactions in combination with other cells of the adaptive and the innate immune system. Starting from a naive cell, CD4+ T cells can differentiate into various effector cell populations with specialized function. This subset specific differentiation depends on numerous signals and the strength of stimulation. However, recent data have shown that differentiated CD4+ T cell subpopulations display a high grade of plasticity and that their initial differentiation is not an endpoint of T cell development. In particular, FoxP3+ regulatory T cells (Treg) and Th17 effector T cells demonstrate a high grade of plasticity, which allow a functional adaptation to various physiological situations during an immune response. However, the plasticity of Treg and Th17 cells might also be a critical factor for autoimmune disease. Here we discuss the recent developments in CD4+ T cell plasticity with a focus on Treg and Th17 cells and its role in human autoimmune disease, in particular multiple sclerosis (MS).

Introduction

CD4+ T helper (Th) cells are an essential element of the adaptive immune system, regulating B cell dependent, humoral as well as CD8+ cytotoxic T cell dependent cellular immune responses. Moreover, CD4+ T cells are able to interact with the innate immune system and respond to stimuli in particular from dendritic cells (DC). Upon peptide/MHC-class II TCR mediated antigen encounter, naive CD4+ T cells are activated and differentiate into T effector cells, which can generate long lasting memory T cells. Depending on the antigen and strength of stimulation, cytokine milieu, co-stimulatory and various additional factors, CD4+ T cells can differentiate into distinct subpopulations with specialized functions [1], [2].

Classically, CD4+ T cells were divided into Th1 and Th2 subsets. Th1 cells produce the signature cytokine interferon (IFN)-γ and are induced in the presence of interleukin (IL)-12. They express the specific transcription factor Tbet (TBX21) and are generated in response to viral infections where they provide help to CD8+ T cells. Th2 cells are primarily linked to humoral immune responses by providing B cell help and are induced in the presence of IL-4. Th2 cells express the transcription factor GATA3 and are characterized by the expression of the signature cytokines IL-4, IL-5, and IL-13. However, since the discovery of Th1 and Th2 cells, several additional Th cell subpopulations have been described. So far, the most prominent additions are the FoxP3+ regulatory T cells (Treg) and IL-17 producing Th17 cells. Regulatory T cells are a distinct lineage of CD4+ T cells, generated during thymic development, which play an important role in maintaining peripheral tolerance. While Th17 cells are induced in the presence of transforming growth factor (TGF)-beta and IL-21, IL-6 or IL-1β and play a major role in fighting extracellular pathogens. Importantly, both of the latter populations are believed to play a major role in human autoimmune diseases [1], [3].

Although CD4+ Th cell polarization based on the Th1/Th2 paradigm was believed to be a stable process with low grade of variability, recent data provided evidence that this is not the case for many Th subpopulations. Indeed, under certain circumstances most of the differentiated Th cells and in particular Th17 and Treg cells show a great magnitude of plasticity and are able to change their phenotype and function. In this review we discuss the recent findings about Th cell plasticity with an emphasis on Treg and Th17 cells and their role in the human autoimmune disease MS.

Section snippets

Th17 cells

It is now established that Th17 cells represent, in addition to Th1 and Th2 cells, an independent helper T cell lineage [4], [5]. Th17 cells were initially described based on their secretion of IL-17. They express a series of other cytokines including IL-17F, IL-21, GM-CSF and IL-22 [1]. Their lineage specific transcription factor is the retinoic acid receptor-related orphan receptor γt (RORγt, in humans RORc), which controls development and function of Th17 cells [6]. However, RORγt acts in

Th17 plasticity

It was noted from early on that at least a subset of Th17 cells had the potential to secrete IFN-γ in mice and humans and thus identify a population with Th1-like features [2]. This was surprising, since initial studies have found that IFN-γ can block Th17 development [107]. By using reporter mice for IL-17F this phenomenon was studied in more detail in vitro and in vivo. It was found that the Th17 stability is dependent on TGF-β but is lost in the presence of IL-12, favoring the expression of

Concluding remarks

The plasticity of CD4+ T cells and in particular of Tregs and Th17 cells might have evolved to keep elasticity in combination with stability to enable the immune system to most flexibly deal with pathogens and changes in the environment. However, this flexibility also comprises a potential threat to the host, since the deregulation of this system enhances the risk of developing autoimmunity. It is therefore not surprising that several mechanisms have evolved to control T cell plasticity and

Conflict of interest

The authors declare no competing financial interests.

Acknowledgments

This work was supported by a National MS Society Collaborative Research Center Award CA1061-A-18, National Institutes of Health Grants P01 AI045757, U19 AI046130, U19 AI070352, and P01 AI039671, and by a Jacob Javits Merit award (NS2427) from the National Institute of Neurological Disorders and Stroke, the Penates Foundation and the Nancy Taylor Foundation for Chronic Diseases, Inc. (to D.A.H.). The authors would like to thank S. Ni Choileain for critical reading of the manuscript.

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