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Regulatory lymphocytes

Regulatory T cells in transplantation tolerance

Nature Reviews Immunology volume 3, pages 199–210 (2003)Cite this article

Key Points

  • Regulation by CD4+CD25+ T cells is one of the mechanisms used in vivo to both induce and maintain transplantation tolerance.

  • Alloantigen-specific regulatory T (TReg) cells can be generated either in vivo or ex vivo.

  • TReg cells are found in the graft, as well as in the peripheral lymphoid tissues, after transplantation.

  • Alloantigen-specific and naturally occurring CD4+CD25+ TReg cells use similar mechanisms to control immune responsiveness in vivo.

  • Alloantigen-specific TReg cells can be augmented by exposure to alloantigen.

  • CD4+CD25+ TReg cells are one form of immunoregulation used to control responsiveness to alloantigens; the relationships between CD4+CD25+ TReg cells and other populations of regulatory cells remain to be clarified.

Abstract

The identification and characterization of regulatory T (TReg) cells that can control immune responsiveness to alloantigens have opened up exciting opportunities for new therapies in transplantation. After exposure to alloantigens in vivo, alloantigen-specific immunoregulatory activity is enriched in a population of CD4+ T cells that express high levels of CD25. In vivo, common mechanisms seem to underpin the activity of CD4+CD25+ TReg cells in both naive and manipulated hosts. However, the origin, allorecognition properties and molecular basis for the suppressive activity of CD4+CD25+ TReg cells, as well as their relationship to other populations of regulatory cells that exist after transplantation, remain a matter of debate.

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Figure 1: Regulatory T cells can control immune responsiveness in vivo.
Figure 2: Linked unresponsiveness as a mechanism of immunoregulation in transplantation.
Figure 3: Origin of alloantigen-specific regulatory T cells.
Figure 4: Potential effector mechanisms of regulatory T cells.
Figure 5: Potential ways of manipulating regulatory T cells in transplantation.

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Acknowledgements

K.J.W. holds a Royal Society Wolfson Research Merit Award. Work in K.J.W.'s laboratory is funded by The Wellcome Trust, the National Kidney Research Fund and the Roche Organ Transplant Research Foundation. The research of S.S. is supported by the Ministry of Education, Science, Sports and Culture, Japan.

Author information

Authors and Affiliations

  1. Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK

    Kathryn J. Wood

  2. Department of Experimental Pathology, Institute of Frontier Medical Sciences, Kyoto University, Japan

    Shimon Sakaguchi

Authors
  1. Kathryn J. Wood
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  2. Shimon Sakaguchi
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Correspondence to Kathryn J. Wood.

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DATABASES

LocusLink

CCL1

CCL4

CCL17

CCL22

CCR4

CCR5

CCR8

CD4

CD8

CD25

CD28

CD45

CD103

CD122

CTLA4

FOXP3

GITR

IFN-γ

IL-2

IL-10

TGF-β

OMIM

IPEX

FURTHER INFORMATION

Immune Tolerance Network

Kathryn Wood's lab

Shimon Sakaguchi's lab

Glossary

OPERATIONAL TOLERANCE

An antigen-specific unresponsiveness that is sustained in the absence of chronic immunosuppression.

NATURAL KILLER T CELLS

(NKT cells). These are distinct from conventional T cells and express natural killer-cell receptors in addition to an invariant T-cell receptor, Vα14–Jα18, which enables them to recognize glycolipids presented by CD1.

GRAFT-VERSUS-HOST DISEASE

(GVHD). An immune response mounted against the recipient of an allograft by donor T cells derived from the graft. Typically, it is seen in the context of allogeneic bone-marrow transplantation.

ORAL TOLERANCE

Oral administration of antigen or peptide with the aim of inducing specific immunological unresponsiveness.

CO-STIMULATION BLOCKADE

Inhibition of the additional or second signals that are required for the activation of T and B cells. The two pathways that have attracted interest in the setting of transplantation are the CD28 and CD154 pathways. CD28 is a key co-stimulatory signal for T cells that can be blocked by the fusion protein CTLA4–immunoglobulin, whereas CD154–CD40 interactions have a role in both T- and B-cell activation and can be inhibited by blocking monoclonal antibodies specific for CD154.

1α, 25-DIHYDROXYVITAMIN D3

The active form of the naturally occurring molecule vitamin D3, which has immunosuppressive properties owing to its ability to modify the function of dendritic cells.

MYCOPHENOLATE MOFETIL

An anti-proliferative, immunosuppressive agent.

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Wood, K., Sakaguchi, S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 3, 199–210 (2003). https://doi.org/10.1038/nri1027

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