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  • Review Article
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Regulatory lymphocytes

Antigen-induced regulatory T cells in autoimmunity

Nature Reviews Immunology volume 3, pages 223–232 (2003)Cite this article

Key Points

  • It is possible that antigen-specific regulatory T (TReg) cells can be induced to prevent or treat autoimmune diseases.

  • The effector functions of antigen-induced TReg cells cannot be defined uniformly and have to be analysed in relation to the disease process that they suppress.

  • So far, TReg cells can only be classified and detected according to their in vivo regulatory effector functions, such as cytokine production, and not by the expression of specific cell-surface markers.

  • Bystander suppression mediated by interleukin-4 (IL-4) and IL-10 (and possibly other cytokines) that can lead to the modulation of antigen-presenting cell function seems to be the main effector mechanism of antigen-induced TReg cells for suppressing autoaggressive T cells in vivo.

  • Although clinical applications of TReg cells are feasible, conditions for their induction need to be better defined, in part to avoid the concomitant augmentation of autoaggressive T cells. The ability to track TReg cells in peripheral blood will be essential.

  • Both mucosal and systemic routes of immunization can induce TReg cells.

  • Antigen-induced TReg cells might contribute to the homeostatic balance of the immune system.

  • Antigen-induced TReg cells escape thymic negative selection and recognize autoantigens, but they proliferate poorly compared with autoaggressive effector T cells.

  • Antigen-induced TReg cells do not necessarily express CD25 and are, therefore, distinct from CD4+CD25+ 'naturally occurring' TReg cells.

  • The use of immunodeficient hosts to 'read-out' TReg-cell function in vivo makes it difficult to distinguish between active regulatory function and homeostatic effects.

Abstract

The ultimate goal of any treatment for autoimmune diseases is antigen- and/or site-specific suppression of pathology. Autoaggressive lymphocytes need to be eliminated or controlled to prevent tissue damage and halt the progression of clinical disease. Strong evidence is emerging that the induction of regulatory T (TReg) cells by autoantigens can suppress disease, even if the primary, initiating autoantigens are unknown and if inflammation is progressive. An advantage of these autoreactive TReg cells is their ability to act as bystander suppressors and dampen inflammation in a site-specific manner in response to cognate antigen expressed locally by affected tissues. In this review, we consider the nature and function of such antigen-specific TReg cells, and strategies for their therapeutic induction are discussed.

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Figure 1: Antigen presentation and pathways to functional tolerance.
Figure 2: Difficulties in identifying CD25+-lineage-derived TReg cells in immune hosts and with equating expression of CD25 with TReg-cell function.
Figure 3: Local bystander suppression.
Figure 4: Hypothetical model of the balance between autoaggressor and autoregulator T cells in autoimmune disease.

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Acknowledgements

We thank D. Frye and C. O'Shea for excellent help with manuscript preparation. M.G.V. is supported by grants from the National Institutes of Health and the Juvenile Diabetes Research Foundation (JDRF). L.C.H. is supported by grants from the JDRF and the National Health and Medical Research Council of Australia.

Author information

Authors and Affiliations

  1. Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, 92121, California, USA

    Matthias G. von Herrath

  2. Autoimmunity and Transplantation Division, Walter Eliza Hall Institute of Medical Research, Parkville, 3050, Victoria, Australia

    Leonard C. Harrison

Authors
  1. Matthias G. von Herrath
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DATABASES

LocusLink

CD1

CD3

CD4

CD8

CD25

CD45

CD62L

CD154

CTLA4

GAD

GITR

IL-2

IL-4

IL-10

MBP

TGF-β

OMIM

multiple sclerosis

rheumatoid arthritis

type 1 diabetes

FURTHER INFORMATION

Leonard Harrison's lab

Matthias von Herrath's lab

Glossary

CO-STIMULATORY SIGNAL

Signalling through an additional molecule that contributes to complete T-cell activation after the T-cell receptor recognizes the peptide–MHC complex.

ALTERED PEPTIDE LIGAND

(APL). A peptide ligand with a different sequence to the native ligand that can alter the interaction between the peptide–MHC complex and the T-cell receptor, and thereby affect lymphocyte activation and effector functions.

BYSTANDER SUPPRESSION

The ability of a lymphocyte with specificity for antigen A to suppress immune responses to an unrelated antigen B.

TR1 cells

Interleukin-10 (IL-10)-secreting human CD4+ cells, the in vitro propagation of which is enhanced by IL-10 and interferon-α TR1 cells have been shown to regulate alloreactive lymphocyte responses in vitro and they are currently being used in clinical trials for the treatment of graft-versus-host disease. However, the mechanisms of their antigen-specific induction remain unclear.

IMMUNE SYNAPSE

A structure that is formed at the cell surface between a T cell and an antigen-presenting cell; also known as a supra-molecular activation cluster (SMAC). The T-cell receptor and numerous signal-transduction molecules and molecular adaptors accumulate at this site. Mobilization of the actin cytoskeleton of the cell is required for formation of the synapse.

PROFESSIONAL ANTIGEN-PRESENTING CELL

A cell that is capable of providing co-stimulation through CD80/CD86, CD40 and other molecules, in addition to presenting antigen in the context of MHC molecules. This category includes dendritic cells, B cells and macrophages.

INTRAEPITHELIAL LYMPHOCYTES

(IELs). Lymphocytes that are found in the epithelial lining of the gut.

ORAL TOLERANCE

The suppression of systemic immune responses to an antigen after its prior administration through a mucosal (classically oral) route.

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von Herrath, M., Harrison, L. Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol 3, 223–232 (2003). https://doi.org/10.1038/nri1029

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