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CD4+CD25+ suppressor T cells: more questions than answers

Key Points

  • Although the concept of suppression mediated by T cells was proposed originally 30 years ago, recent studies in animal models of autoimmunity have rekindled interest in the existence of a subset of lymphocytes that specifically suppress immune responses.

  • Some T cells that have suppressor activity are part of a unique lineage of CD4+ T cells that are 'naturally occurring' and are present in the thymus and peripheral lymphoid tissues of mice and humans. Other types of suppressor T cell can be induced from conventional CD4+ T cells by specific experimental manipulations in vitro.

  • The 'naturally occurring' suppressor T-cell population can be identified by expression of the CD25 antigen. However, CD25 can be expressed by any activated T cell, so it cannot be used as a suppressor-cell marker after perturbation of the immune system.

  • CD4+CD25+ T cells are potent suppressors of the activation of both CD4+ and CD8+ T cells in vitro. Suppression is mediated by a cell-contact-dependent, cytokine-independent mechanism.

  • CD4+CD25+ T cells are also potent suppressors of a large number of animal models of autoimmunity, including gastritis, thyroiditis, inflammatory bowel disease and insulin-dependent diabetes mellitus. Both suppressor cytokines — such as interleukin-4 (IL-4), IL-10 and transforming growth factor-β — and a cell-contact-dependent mechanism might have a role in the suppression of disease in vivo.

  • In vitro, CD4+CD25+ T cells can mediate suppression by acting solely on responder CD4+CD25 effector cells. It remains possible that other cell types (such as antigen-presenting cells, B cells and natural killer cells) might also be targets of suppression, particularly in vivo.

  • CD4+CD25+ T cells require IL-2 for their differentiation in the thymus and for their survival and maintenance in peripheral lymphoid tissues. Their physiological target antigen is unknown, but some studies indicate that they might recognize antigens from the target organ in organ-specific autoimmunity.

  • Cells that have suppressor activity can be generated from CD4+CD25 cells by stimulation under conditions in which co-stimulation is limiting (in the presence of IL-10 or immature dendritic cells). Most frequently, these induced suppressors function by secreting suppressor cytokines, such as IL-10.

  • The enhancement of suppressor-cell function might be a target for immunotherapeutic approaches for the treatment of autoimmunity. By contrast, the elimination of suppressor cells or the inhibition of their function might prove to be useful for the induction of tumour immunity or the treatment of chronic infectious diseases.

Abstract

Several mechanisms control discrimination between self and non-self, including the thymic deletion of autoreactive T cells and the induction of anergy in the periphery. In addition to these passive mechanisms, evidence has accumulated for the active suppression of autoreactivity by a population of regulatory or suppressor T cells that co-express CD4 and CD25 (the interleukin-2 receptor α-chain). CD4+CD25+ T cells are powerful inhibitors of T-cell activation both in vivo and in vitro. The enhancement of suppressor-cell function might prove useful for the treatment of immune-mediated diseases, whereas the downregulation of these cells might be beneficial for the enhancement of the immunogenicity of vaccines that are specific for tumour antigens.

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Figure 1: Many types of suppressor T cell exist in the normal host.
Figure 2: What role does CTLA4 have in CD4+CD25+ T-cell function?
Figure 3: What is the target cell for CD25+ T-cell-mediated suppression?
Figure 4: CD25+ T cells mediate protection from autoimmune disease by cytokine-dependent and -independent pathways.
Figure 5: Depletion of CD25+ T cells is not sufficient for the induction of autoimmunity.
Figure 6: CD25+ T cells differentiate in the thymus.

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Acknowledgements

I would like to thank A. Thornton, R. McHugh and C Piccirillo for their hard work and stimulating discussions.

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DATABASES

CancerGov

melanoma

Entrez

influenza-virus haemagglutinin

Interpro

TNF family

Locuslink

CCL4

CCR4

CCR5

CCR8

CD3

CD25

CD28

CD80

CD86

CTLA4

gastric H/K ATPase

IFN-α

IFN-γ

IL-2

Il2

IL-4

Il4

IL-10

Il10

Il2rb

Mbp

Rag

Smad3

TGF-β

TGFβRII

TNFRSF8

Medscape DrugInfo

mycophenolate mofetil

OMIM

inflammatory bowel disease

Glossary

INFLAMMATORY BOWEL DISEASE

(IBD). A T-cell-mediated inflammatory response that affects the small and large bowel, resembling Crohn's disease in humans. In the mouse model, most of the inflammation is confined to the large bowel. The target antigen that is recognized by the pathogenic T cells is unknown.

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIF

(ITIM). A structural motif containing tyrosine residues that is found in the cytoplasmic tails of several inhibitory receptors, such as FcγRIIB and PIRB. The prototype six-amino-acid ITIM sequence is (Ile/Val/Leu/Ser)-Xaa-Tyr-Xaa-Xaa-(Leu/Val). Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family tyrosine kinases, which provides a docking site for the recruitment of cytoplasmic phosphatases that have an SH2 domain.

AUTOIMMUNE GASTRITIS

(AIG). The destruction of gastric parietal cells by CD4+ T cells that recognize the proton pump, the H/K ATPase, that is expressed by parietal cells. It is an animal model of the human disease pernicious anaemia.

LYMPHOPAENIC MICE

A loss of both T and B cells, as is seen in SCID or Rag-deficient mice that lack an enzyme that is required for the generation of T- and B-cell receptors, or a loss of T cells only, as seen in nu/nu mice, which lack a thymus. A relative T-cell lymphopaenia can be seen when mice are thymectomized on day three of life.

NEGATIVE SELECTION

One step in the process of T-cell differentiation in the thymus in which T cells that express high-affinity receptors for self-antigens are eliminated from the repertoire by apoptosis after recognition of their target antigen on thymic medullary dendritic cells.

K14 TRANSGENIC MICE

First, mice that lack all MHC class II antigens are generated. Transgenic mice in which MHC class II antigens are expressed under the control of the keratin promoter are then generated from these deficient mice. MHC class II antigens are expressed solely by cells that can turn on expression of the keratin gene —primarily, epidermal cells and thymic cortical epithelial cells.

ACTIVATION-INDUCED CELL DEATH

(AICD). The normal physiological mechanism by which T cells that are specific for foreign antigen are eliminated from the T-cell repertoire.

NON-OBESE DIABETIC MICE

(NOD mice). A strain of mice that normally develop idiopathic autoimmune diabetes that closely resembles type I diabetes in humans. The target antigen(s) that is recognized by the pathogenic CD4+ T cells that initiate disease is expressed by pancreatic islet cells, but its identity has remained elusive.

EXPERIMENTAL ALLERGIC (OR AUTOIMMUNE) ENCEPHALOMYELITIS

(EAE). An animal model of multiple sclerosis — a chronic demyelinating disease in humans. In animals, EAE is induced by the injection of several different antigens that are derived from the myelin sheath, including myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein, together with a potent adjuvant.

INFECTIOUS TOLERANCE

After the activation of suppressor T cells in one animal, suppression can often be transferred to a naive recipient. In some models, this results in the induction of recipient-derived suppressor T cells. Tolerance can then be transferred to a new recipient, leading to the further induction of recipient-derived suppressors. In many respects, this is the 'holy grail' of transplantation immunology.

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Shevach, E. CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2, 389–400 (2002). https://doi.org/10.1038/nri821

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