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Regulatory immune cells in transplantation

Nature Reviews Immunology volume 12, pages 417–430 (2012)Cite this article

Subjects

Key Points

  • The presence of regulatory immune cells in transplant recipients can shift the balance away from rejection and towards immune regulation.

  • Different populations of T cells with regulatory activity have a role in promoting transplant tolerance. These populations include CD4+ regulatory T (TReg) cells, CD8+ TReg cells, CD4−CD8− T cells, natural killer T (NKT) cells and γδ T cells.

  • Control of allograft rejection and graft-versus-host disease (GVHD) can also be enhanced by various non-T cell leukocytes, including regulatory B cells, tolerogenic dendritic cells (DCs), regulatory macrophages, myeloid-derived suppressor cells (MDSCs) and mesenchymal stromal cells (MSCs).

  • Distinct regulatory cell populations are present in the draining lymphoid tissue and in the peripheral blood. These cells migrate to the allograft, where they modulate immune responses by inhibiting effector cells and by inducing other regulatory cells. Early after transplantation, MDSCs and MSCs can migrate to the site of an inflammatory response and promote the development of tolerogenic DCs and macrophages that induce peripheral TReg cell development.

  • Cellular therapies using TReg cells, regulatory macrophages and MSCs are being developed for clinical application to control rejection or GVHD in transplant recipients.

Abstract

Immune regulation is fundamental to any immune response to ensure that it is appropriate for the perceived threat to the host. Following cell and organ transplantation, it is essential to control both the innate immune response triggered by the injured tissue and the adaptive immune response stimulated by mismatched donor and recipient histocompatibility antigens to enable the transplant to survive and function. Here, we discuss the leukocyte populations that can promote immune tolerance after cell or solid-organ transplantation. Such populations include regulatory T cells, B cells and macrophages, as well as myeloid-derived suppressor cells, dendritic cells and mesenchymal stromal cells. We consider the potential of these regulatory immune cells to develop and function in transplant recipients and their potential use as cellular therapies to promote long-term graft function.

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Figure 1: Mechanisms used by adaptive regulatory immune cells in transplantation.
Figure 2: Mechanisms used by regulatory populations of innate immune cells in transplantation.
Figure 3: Potential clinical applications of therapies based on regulatory immune cells.

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Acknowledgements

The work from the authors' own laboratory described in this Review was supported by grants from the Wellcome Trust, the UK Medical Research Council, the British Heart Foundation, the Roche Organ Transplant Research Foundation and the European Union (through the Indices of Tolerance, RISET, ONE Study and OptiStem projects). The authors would like to thank all members of the Transplantation Research Immunology Group past and present for their valuable contributions to the data reviewed herein, and particularly R. Goto for help with the figure outlines.

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  1. Nuffield Department of Surgical Sciences, Transplantation Research Immunology Group, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Kathryn J. Wood, Andrew Bushell & Joanna Hester

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Correspondence to Kathryn J. Wood.

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Glossary

Graft-versus-host disease

(GVHD). Tissue damage that occurs in a recipient of allogeneic transplanted tissue (usually a bone marrow transplant) as a result of the activity of donor cytotoxic T lymphocytes that recognize the tissue of the recipient as foreign. GVHD varies markedly in severity, but can be life threatening in severe cases. Typically, damage to the skin and gut mucosa leads to clinical manifestations.

Mixed chimerism

A state of coexistence of host and allogeneic donor haematopoietic cells.

Natural killer T cells

(NKT cells). A subset of T cells expressing both NK cell and T cell markers. In mice, NKT cells were first identified by their expression of the alloantigen NK1.1 (NK cell-associated antigen 1.1) in addition to CD3. Some mouse NKT cells express an invariant T cell receptor (TCR) containing the Vα14 variable region of the TCR α-chain and recognize antigens presented on CD1d. Similarly, human NKT cells express an invariant Vα24-containing TCR. NKT cells are characterized functionally by cytolytic activity and the rapid production of cytokines, including IFNγ and IL-4.

Ischaemia–reperfusion injury

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. The restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.

Induction therapy

A therapy given before transplantation to promote graft acceptance.

Trogocytosis

A process whereby lymphocytes that are interacting with an antigen-presenting cell (APC) can extract cell-surface molecules expressed by the APC and display them on their own surface.

Graft-versus-tumour response

An immune response mounted against host tumour cells by donor T cells (mainly cytotoxic CD8+ T cells) that are derived from an allogeneic bone marrow transplant.

Plasmacytoid DC

(pDC). An immature dendritic cell (DC) with a morphology that resembles that of a plasma cell. pDCs produce large amounts of type I interferons in response to viral infection.

Transitional B cells

Transitional B cells are short-lived immature B cells, typically found in the spleen, that either die or are selected into the peripheral mature B cell repertoire. Transitional B cells can be subdivided into three subsets (T1, T2 and T3 cells) based on different phenotypical and functional characteristics.

Alternatively activated macrophages

Macrophages that are induced by TH2-type cytokines, such as IL-4 and IL-3, and that are associated with immune responses to parasites and tissue-repair programmes.

B-1 cells

IgMhiIgDlowMAC1+B220lowCD23− cells that are predominantly found in the peritoneal and pleural cavities. The size of the B-1 cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete IgM antibodies that tend to be of low affinity and broad specificity.

Anti-thymocyte globulin

Polyclonal antibodies specific for human T cells that are produced by immunizing rabbits or horses.

Calcineurin inhibitor

An immunosuppressive drug that blocks calcineurin (a phosphatase that is necessary for the nuclear translocation of the transcription factor NFAT) and thus restricts T cell activation.

Graft-versus-leukaemia effect

The antitumour activity of donor T cells against residual leukaemic cells of the graft recipient following allogeneic bone marrow transplantation.

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Wood, K., Bushell, A. & Hester, J. Regulatory immune cells in transplantation. Nat Rev Immunol 12, 417–430 (2012). https://doi.org/10.1038/nri3227

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