Review article
Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease

https://doi.org/10.1016/j.jneuroim.2007.11.016Get rights and content

Abstract

The role of T regulatory (Treg) cells expressing the forkhead box transcription factor 3 (foxp3) in the control of autoaggressive immune responses is the subject of intense investigation. Here we explore the contribution of these cells to the regulation of experimental autoimmune encephalomyelitis (EAE). Starting from a historical perspective, we review their roles in preventing spontaneous disease, in setting the threshold for activation of a pathogenic response and in critically mediating the natural recovery from EAE. Current uncertainties and controversies are discussed in regard to EAE and multiple sclerosis as well as the potential for Treg-targeted immunotherapy.

Introduction

Experimental autoimmune encephalomyelitis (EAE) has been the primary model of central nervous system (CNS) autoimmune disease for over half a century. Its study provides an important developmental history of the concepts and experiments informing our understanding of how the immune system can regulate an autoimmune disease. Several features of the model make it particularly suitable for these studies. Disease can be induced either by immunization with CNS-derived autoantigen in complete Freund's adjuvant (CFA) (active induction), or via the transfer of recently restimulated T cells that recognize myelin autoantigens (passive induction). Activated CD4+ T cells initiate disease which, in the most extensively studied models, involves an acute episode of paralysis that spontaneously resolves, leaving in its wake a resistance to the reinduction of disease. The fact that the transfer of CD4+ T cells alone can initiate disease indicates that the regulation of their trafficking and effector function could potentially influence the threshold for disease development, the severity of disease expression and clinical resolution. The self-limiting nature of disease dramatically illustrates the existence of a regulatory network capable of suppressing vigorous autoaggressive responses. Furthermore, the resistance imprinted by clinical disease demonstrates that this regulation can be actively strengthened. The induction, expansion and maintenance of a putative suppressor/regulatory population in EAE has been the subject of intense study. When so much current immunological research is focused on foxp3+ T regulatory (Treg) cell biology it is illuminating to place T cell-mediated regulation of EAE in the historical context. Here we consider the development of our knowledge of Treg activity in EAE, illustrating the convergence of past and present researches while highlighting those areas that remain controversial.

Section snippets

Suppressor T cells in EAE

An extensive literature has evolved on immune-regulation in EAE. In terms of T cell-mediated regulation however, two models provide the framework for many of the early studies; the development of specific resistance to disease induction in response to immunization with autoantigen in incomplete Freund's adjuvant (IFA) (Szvet-Moldavskaya and Svet-Moldavsky, 1958), and the emergence of a suppressive cell population during the resolution of clinical disease (Adda et al., 1977). In both these

Tregs can limit spontaneous and actively-induced EAE

Before the identification of foxp3 as a Treg-specific transcription factor (Fontenot et al., 2005) surface expression of CD25 was commonly used to identify Tregs. Although CD25 is also expressed at high levels on activated effector T cells, expression in unmanipulated naïve animals, coupled with a demonstration of in vitro suppressive activity, allowed the operational identification of Treg populations (Itoh et al., 1999, Suri-Payer et al., 1998). As a result, the prime experimental strategies

Tregs have a major role in the natural recovery from actively-induced EAE

Clearly MS is not a single disease. That said, when viewed as a whole, a striking feature of MS compared with some other autoimmune diseases is that perhaps as many as 80% of patients will initially present with a relatively benign relapsing–remitting disease course (although around half of these will ultimately convert to a secondary progressive form). This suggests that, at least initially, most sufferers have the capacity to limit their inflammatory episodes (this may or may not be via

The need for optimal Treg depletion strategies

An outstanding issue in the study of Treg function in EAE is the need for a reliable means to specifically and completely deplete the Treg compartment. The constitutive expression of CD25 has allowed the use of anti-CD25 antibody (particularly clone PC61) for depletion studies as described above. A recent study has questioned whether such an approach really leads to depletion of Tregs and presented data (derived chiefly from the use of a different anti-CD25 antibody, namely 7D4) to make the

What does the study of Tregs in EAE tell us about Tregs in MS?

Extrapolation of in vivo data regarding Tregs in EAE to the situation in MS is problematic. Indeed, the data from ourselves and other groups that point to Tregs actively influencing recovery in EAE are somewhat at odds with early studies analysing the function of CD4+CD25hi cells in MS. These report that there is no numerical Treg deficiency in MS patients compared to healthy controls, but that there is a clear defect in their capacity to suppress the proliferation, or IFN-γ production of

Treg-based therapy: a realistic aim?

If Tregs are such potent suppressors of EAE both at the priming stage in the lymph node and in driving the switch to disease remission (most probably in the CNS), can we make use of them therapeutically? In essence, this might be achieved by two approaches. The first would be to isolate Tregs, expand their numbers in culture and reintroduce them, with the idea that an increase in overall frequency might influence ongoing disease. Proof of principle for this approach was provided when

Concluding remarks

In summary, recent observations on the natural and enforced regulation of EAE have advanced our understanding of the dynamic interplay of pathogenic and regulatory cells and of some of the mechanisms behind this. The use of improved immunological tools (such as peptide–MHC multimers, transfer models using genetically-modified cells and cell-specific ablation of function foxp3 expression (Fontenot et al., 2005, Kim et al., 2007, Reddy et al., 2003), will no doubt allow rapid further advances

Acknowledgements

Work in the authors' laboratory is supported by grants from the Medical Research Council (UK), the Wellcome Trust and the UK Multiple Sclerosis Society. SMA is an MRC Senior Research Fellow.

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