The role of FOXP3 in autoimmunity

doi:10.1016/j.coi.2016.07.004

Current Opinion in Immunology

Volume 43, December 2016, Pages 16-23

https://doi.org/10.1016/j.coi.2016.07.004 Get rights and content

Highlights

•
Dysregulation of FOXP3 expression can occur at multiple levels in autoimmunity.
•
Autoimmune SNPs diminish IL-2 sensitivity and FOXP3, resulting in impaired Tregs.
•
Splicing, post-translational modification, and subcellular localization regulate FOXP3.
•
Many new Treg-targeted therapies are being tested in autoimmunity.

FOXP3 controls the development and function of T regulatory cells (Tregs). Autoimmunity is linked to changes in FOXP3 activity that can occur at multiple levels and lead to Treg dysfunction. For example, changes in IL-2 signaling, FOXP3 transcription and/or post-translational modifications can all contribute to loss of self-tolerance. As additional pathways of FOXP3 regulation are elucidated, new therapeutic approaches to increase Treg activity either by cell therapy or pharmacological intervention are being tested. Early success from pioneering studies of Treg-based therapy in transplantation has promoted the undertaking of similar studies in autoimmunity, with emerging evidence for the effectiveness of these approaches, particularly in the context of type 1 diabetes.

Introduction

Forkhead box protein 3 (FOXP3) is the master transcription factor for CD4⁺ regulatory T cells (Tregs) [1], a cell type that plays a critical role in immune regulation. The essential role of FOXP3 and Tregs in autoimmunity was discovered through studies of humans with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome and the scurfy mouse model [2]. IPEX patients and scurfy mice have monogenic mutations in FOXP3 causing absent or poorly functional FOXP3 protein, a lack of normal Tregs, and the consequent development of multi-system autoimmunity [2].

Following these seminal studies in primary immunodeficiencies, many groups investigated whether changes in FOXP3 and associated changes in Treg numbers or function might also underlie the common polygenic forms of autoimmunity. Indeed there is now ample evidence that FOXP3 can be dysregulated in many ways, leading to altered Tregs that initiate and/or perpetuate autoimmunity. Here we review advances made in our understanding of how FOXP3 regulates autoimmunity, focusing on research in humans in the past 2 years addressing two main questions: firstly, how is FOXP3 dysregulated in autoimmunity? and secondly, how can FOXP3 be therapeutically targeted to treat autoimmunity?

Section snippets

How is FOXP3 dysregulated in autoimmunity?

Autoimmunity is clearly associated with changes in the proportion and/or function of FOXP3-expressing Tregs [3], but there is no dominant mechanism driving these changes. Rather, factors affecting Treg function range from the effects of genetics, to changes in FOXP3-promoting signaling pathways, FOXP3 mRNA expression, or protein modification, summarized in Figure 1. Autoimmunity may be driven by one or more of these mechanisms, ultimately resulting in disrupted balance between Tregs and

How can FOXP3 be targeted in autoimmunity?

With more than a decade of evidence that poor FOXP3 expression and Treg function causes or perpetuates autoimmunity, a variety of approaches to reverse these phenomena have been explored. The approaches are broadly classified as cellular or non-cellular treatments, with a combined approach likely being the most effective.

Conclusions and perspective

How autoimmunity is affected by changes in FOXP3 as it specifically relates to CD4⁺ Tregs has been extensively studied, but it is important to note that FOXP3 also has regulatory roles in other immune cells. Activated CD4⁺ T cells express FOXP3, leading to restraint of cytokine production and proliferation [64^•], and there are also reports of FOXP3 expression in CD8⁺ and invariant NKT cells. Whether or not autoimmunity is linked to changes in FOXP3 in non-CD4⁺ Tregs is an underexplored area of

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

The authors’ own work on FOXP3 and autoimmunity is supported by grants from the Canadian Institutes for Health Research, the Canucks for Kids Foundation, and JDRF. AMP holds fellowships from the CIHR-STIR Training program in Transplantation, the 4 What Matters foundation fellowship and the JDRF postdoctoral fellowship. LC holds a fellowship from the JDRF Canadian Clinical Trial Network. MKL receives a Scientist Salary Award from the BC Children's Hospital Research Institute. We thank Dr. Paul

References (69)

X. Li et al.
Regulatory T cell identity: formation and maintenance
Trends Immunol
(2015)
R.M. Pacheco-Gonzalez et al.
Analysis of FOXP3 gene in children with allergy and autoimmune diseases
Allergol Immunopathol (Madr)
(2016)
C.W. Li et al.
Dissecting the role of the FOXP3 gene in the joint genetic susceptibility to autoimmune thyroiditis and diabetes: a genetic and functional analysis
Gene
(2015)
K. Cerosaletti et al.
Multiple autoimmune-associated variants confer decreased IL-2R signaling in CD4+ CD25(hi) T cells of type 1 diabetic and multiple sclerosis patients
PLoS One
(2013)
V.K. Sharma et al.
Impaired regulatory T cell function in autoimmune diseases: are microRNAs the culprits?
Cell Mol Immunol
(2016)
Y. Zhang et al.
MicroRNAs in CD4(+) T cell subsets are markers of disease risk and T cell dysfunction in individuals at risk for type 1 diabetes
J Autoimmun
(2016)
M. DuPage et al.
The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation
Immunity
(2015)
J.D. Goldstein et al.
Inhibition of the JAK/STAT signaling pathway in regulatory T cells reveals a very dynamic regulation of Foxp3 expression
PLoS One
(2016)
J. van Loosdregt et al.
Rapid temporal control of Foxp3 protein degradation by sirtuin-1
PLoS One
(2011)
M. Sarumaru et al.
Association between functional SIRT1 polymorphisms and the clinical characteristics of patients with autoimmune thyroid disease
Autoimmunity
(2016)

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³: These authors contributed equally to the work.

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The role of FOXP3 in autoimmunity

Highlights

Introduction

Section snippets

How is FOXP3 dysregulated in autoimmunity?

How can FOXP3 be targeted in autoimmunity?

Conclusions and perspective

References and recommended reading

Acknowledgements

Trends Immunol

Allergol Immunopathol (Madr)

Gene

PLoS One

Cell Mol Immunol

J Autoimmun

Immunity

PLoS One

PLoS One

Autoimmunity

J Pediatr Endocrinol Metab

J Biol Chem

Nat Med

Sci Transl Med

Blood

Cell Mol Immunol

Blood

Ann Rheum Dis

Immunity

Immunity

Eur J Immunol

J Immunol

Sci Transl Med

Diabetes

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Genetic and epigenetic fine mapping of causal autoimmune disease variants

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Natural variation in IL-2 sensitivity influences regulatory T cell frequency and function in individuals with long-standing type 1 diabetes

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Genetics of autoimmune diseases: perspectives from genome-wide association studies

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Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms

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