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  • Review Article
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Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases

Key Points

  • There is evidence of impaired regulation by CD4+CD25+FOXP3+ regulatory T (TReg) cells in the human autoimmune diseases type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis.

  • Causes of this impaired tolerance include: inadequate numbers of TReg cells, TReg cell-intrinsic defects and factors extrinsic to TReg cells that allow escape from suppression, including the resistance of effector T cells to suppression and factors present in the inflammatory milieu, such as cytokines and antigen-presenting cells.

  • The approaches by which these mechanisms of failed tolerance can be pursued must take into account how best to 'count' TReg cells and how to carry out functional suppression assays using human samples.

  • Multiple studies that enumerate TReg cells in the peripheral blood have been carried out, but interpretation of these studies is difficult owing in part to inconsistency in marker usage. Despite these limitations, increased numbers of TReg cells have been seen consistently in disease tissues.

  • In vitro suppression cultures consistently show defects in TReg cell-mediated suppression in autoimmune diseases, with the exception of inflammatory bowel disease.

  • Resistance of effector T cells to suppression has been identified in type 1 diabetes, systemic lupus erythematosus and psoriasis.

  • Future studies that will enhance our understanding of the role of TReg cells in the development of autoimmunity should include improved analysis of the subsets of T cells with a CD4+CD25+FOXP3+ phenotype, as well as improved measures of suppression that will take into account factors that may be present in vivo at the site of inflammation, including the local antigen-presenting cells and cytokine environment.

  • In summary, defects in the number and suppressive function of CD4+CD25+FOXP3+ TReg cells have been identified in individuals with autoimmune disease. These findings now need to be extended to define the molecular mechanisms by which this form of tolerance is lost in the hope that this will guide the future development of therapies for these diseases.

Abstract

A lack of regulatory T (TReg) cells that express CD4, CD25 and forkhead box P3 (FOXP3) results in severe autoimmunity in both mice and humans. Since the discovery of TReg cells, there has been intense investigation aimed at determining how they protect an organism from autoimmunity and whether defects in their number or function contribute to the development of autoimmunity in model systems. The next phase of investigation — that is, to define the role that defects in TReg cells have in human autoimmunity — is now underway. This Review summarizes our progress so far towards understanding the role of CD4+CD25+FOXP3+ TReg cells in human autoimmune diseases and the impact that this knowledge might have on the diagnosis and treatment of these diseases.

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Figure 1: Causes of impaired TReg cell-mediated suppression in autoimmunity.

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Acknowledgements

J.H.B. is supported by grants from the US National Institutes of Health, the Juvenile Diabetes Research Foundation and the Alliance for Lupus Research.

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Glossary

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

(IPEX). A disease caused by mutations in the transcription factor forkhead box P3 (FOXP3) and characterized by refractory enteritis and, in some patients, autoimmune endocrinopathies, autoimmune diabetes and thyroiditis. Unlike scurfy mice, peripheral blood mononuclear cells from patients with IPEX fail to produce cytokines after in vitro stimulation.

Scurfy mice

A mouse strain with a spontaneous mutation in the transcription factor forkhead box P3 (FOXP3; also known as scurfin), which leads to a rapidly fatal lymphoproliferative disease, causing death by about 4 weeks of age. FOXP3-deficient mice lack regulatory T cells.

Non-obese diabetic mice

(NOD mice). NOD mice spontaneously develop type 1 diabetes mellitus as a result of autoreactive T cell-mediated destruction of pancreatic islet β-cells.

DO11.10 RIP-mOVA mice

A transgenic mouse model of type 1 diabetes in which a transgene encoding membrane-bound ovalbumin (mOVA) is expressed in the pancreas under the control of the rat insulin promoter (RIP) and therefore acts as a self antigen. Co-expression of a transgenic T cell receptor (DO11.10) in these mice leads to the development of spontaneous diabetes.

Experimental autoimmune encephalomyelitis

(EAE). An experimental mouse model of multiple sclerosis that is induced in susceptible animals by immunization with central nervous system antigens. EAE is an autoimmune disease that is mediated by CD4+ T helper 1 (TH1) cells and interleukin-17-producing TH17 cells that are reactive to components of the myelin sheath. The cells infiltrate the nervous parenchyma, release pro-inflammatory cytokines and chemokines, promote leukocyte infiltration and contribute to demyelination.

MRL–lpr mice

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus. The lpr mutation causes a defect in CD95 (also known as FAS), preventing apoptosis of activated lymphocytes. The MRL strain contributes disease-associated mutations that have yet to be identified.

Crohn's disease

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract but is most common in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation and is thought to result from an abnormal T cell-mediated response to commensal bacteria.

Ulcerative colitis

A mucosal inflammation involving the rectum and extending for a variable distance along the colon.

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Buckner, J. Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases. Nat Rev Immunol 10, 849–859 (2010). https://doi.org/10.1038/nri2889

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