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  • Review Article
  • Published:

Therapeutic opportunities for manipulating TReg cells in autoimmunity and cancer

Nature Reviews Drug Discovery volume 12, pages 51–63 (2013)Cite this article

Subjects

Key Points

  • Dominant tolerance is executed by a committed lineage of CD4+CD25+Foxp3+ regulatory T (TReg) cells.

  • The fact that TReg cells are essential mediators of immune homeostasis has led to the quest for novel therapeutic strategies for targeting these cells in various diseases.

  • In autoimmunity, the induction of specific TReg cells could permit modulation of the immune response for clinical benefit while limiting the effect of long-term general immune suppression.

  • Strategies to promote TReg cell generation include subimmunogenic T cell receptor stimulation using strongly agonistic variants of self-antigens, transforming growth factor-β, inhibitors of the mammalian target of rapamycin (mTOR) pathway as well as microRNAs.

  • Approaches to expand TReg cells include the application of cytokines such as interleukin-2 (IL-2), whereas the manipulation of TReg cell survival and stability can be achieved using phosphoinositide 3-kinase (PI3K)–AKT–mTOR inhibitors or DNA methyltransferase inhibitors.

  • In cancer, the development of agents that specifically inhibit TReg cell function will permit new approaches for anticancer immunotherapy.

  • Blockade of TReg cell expansion can be achieved using tyrosine kinase inhibitors such as imatinib, which can also support the inhibition of the suppressive function of TReg cells.

  • TReg cell-mediated immune suppression can be limited by low doses of cyclophosphamide or by cytotoxic T lymphocyte antigen 4 (CTLA4)-blocking antibodies such as ipilimumab.

  • Combinatorial approaches of antigen-specific and nonspecific strategies, along with an improved understanding of the underlying molecular mechanisms of tolerance, are likely to be required to deal with the complexity of the immune system.

Abstract

Forkhead box P3 (FOXP3)-expressing regulatory T (TReg) cells have a pivotal role in the regulation of immune responses and in the maintenance of immunological self-tolerance. These cells have emerged as attractive targets for strategies that allow the steering of immune responses in desired directions — arming the immune system to destroy infected cells and cancer cells or downregulating it to limit tissue destruction in autoimmunity. Efforts to understand the generation, activation and function of TReg cells should permit the development of therapeutics for reprogramming the immune system. In this Review, we discuss insights into the generation of TReg cells, their involvement in disease and the molecular basis of the dominant tolerance exerted by FOXP3+ TReg cells that could permit their safe and specific manipulation in humans.

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Figure 1: General strategies for the manipulation of regulatory T cells in autoimmunity and cancer.
Figure 2: PI3K–AKT–mTOR signalling to block the generation of Foxp3+ TReg cells.
Figure 3: Possible scheme for S1P–S1PR1-dependent regulation of TReg

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Acknowledgements

The studies were supported by the US National Institutes of Health Grant NIH-AI-53102 (to H.V.B.). C.D. was supported by a Leopoldina research fellowship (BMBF-LPD 9901/8-184) and is now supported by a Junior Research Group at Helmholtz Zentrum München, Germany.

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Authors and Affiliations

  1. Department of Cancer Immunology and AIDS, Laboratory of Lymphocyte Biology, Dana Farber Cancer Institute, 450 Brookline Avenue, Smith 736, Boston, 02115, Massachusetts, USA

    Harald von Boehmer & Carolin Daniel

  2. Harvard Faculty of Arts and Sciences, Harvard University, Cambridge, 02138, Massachusetts, USA

    Harald von Boehmer

  3. Helmholtz Zentrum Muenchen German Center on Environmental Health, Institute of Diabetes Research 1, Ingolstaedter Landstrasse 1, Neuherberg, 85764, München, Germany

    Carolin Daniel

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Glossary

Recessive tolerance

A form of passive tolerance involving clonal deletion (negative selection) and clonal inactivation (anergy), both of which represent cell-intrinsic mechanisms.

Dominant tolerance

The active suppression of an immune response by suppressor cells including regulatory T (TReg) cells. By contrast, deletional tolerance and induction of anergy are forms of passive tolerance. Dominant tolerance is transferable to naive recipients, whereas passive tolerance is not.

Negative selection

Also known as clonal deletion. The intrathymic elimination of CD4+CD8+ double-positive and single-positive thymocytes that express T cell receptors with a high affinity for self-antigens.

Fork-head box P3

(FOXP3). Forkhead or winged helix transcription factor that is expressed primarily in regulatory T (TReg) cells and controls their function. Mutations in the Foxp3 gene result in life-threatening autoimmunity in humans as well as in experimental mice.

Bystander suppression

A situation whereby regulatory T cells of a particular specificity are able to suppress several effector cells with different specificities when colocalized at the same antigen-presenting cell.

Type 1 diabetes

A disorder caused by the autoimmune-mediated destruction of pancreatic islet β-cells, resulting in hyperglycaemia and insulin deficiency at diagnosis.

TNF receptor-associated factor 6

(TRAF6). A protein that is associated with, and mediates, signal transduction from members of the tumour necrosis factor (TNF) receptor superfamily, and also from members of the Toll-like receptor and interleukin-1receptor family. TRAF6 also interacts with various protein kinases, including interleukin-1 receptor-associated kinase 1 (IRAK1).

IL-1R-associated kinase 1

(IRAK1). Along with IRAK2, IRAK1 is a putative serine/threonine kinase that becomes associated with the interleukin-1 receptor (IL-1R) upon stimulation and is responsible for IL-1-induced upregulation of the transcription factor nuclear factor-κB.

Cytotoxic T lymphocyte antigen 4

(CTLA4). A member of the immunoglobulin superfamily. CTLA4 is expressed on the surface of T helper cells and transmits an inhibitory signal to T cells.

CC motif chemokine 22

(CCL22). A protein that is encoded by the CCL22 gene in humans. CCL22 is secreted by dendritic cells and macrophages, and elicits its effects on its target cells by interacting with cell surface chemokine receptors such as CC chemokine receptor 4.

CXC chemokine receptor 4

(CXCR4). An α-chemokine receptor that is specific for CXC motif chemokine ligand 12 (CXCL12; also known as SDF1), a molecule with potent chemotactic activity for lymphocytes.

CXC motif chemokine ligand 12

(CXCL12; also known as SDF1). A small cytokine belonging to the chemokine family, members of which are often induced by pro-inflammatory stimuli such as lipopolysaccharides, tumour necrosis factor or interleukin-1.

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von Boehmer, H., Daniel, C. Therapeutic opportunities for manipulating TReg cells in autoimmunity and cancer. Nat Rev Drug Discov 12, 51–63 (2013). https://doi.org/10.1038/nrd3683

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