Application of Regulatory T Cells in Transplantation Field

Yong-Hee Kim; Hyun-Je Kim; Jung-Sik Kim; Chung-Gyu Park

doi:10.4285/jkstn.2012.26.2.74

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Kim, Kim, Kim, and Park: Application of Regulatory T Cells in Transplantation Field

Review Article

The Journal of the Korean Society for Transplantation

The Journal of the Korean Society for Transplantation 2012; 26(2): 74-82.

Published online: 29 June 2012

DOI: https://doi.org/10.4285/jkstn.2012.26.2.74

Application of Regulatory T Cells in Transplantation Field

Yong-Hee Kim, M.D.^1,^2,^3,⁴, Hyun-Je Kim, M.D.^1,^2,^3,⁴, Jung-Sik Kim, Ph.D.^1,^2,^3,⁴, Chung-Gyu Park, M.D.^1,^2,^3,⁴

¹Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.

²Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.

³Transplantation Research Institute SNUMRC, Seoul National University College of Medicine, Seoul, Korea.

⁴Cancer Research Institute and TIMRC, Seoul National University College of Medicine, Seoul, Korea.

Corresponding author (chgpark@snu.ac.kr)

Received 30 May 2012 Accepted 4 June 2012

Abstract

The development of immunosuppressant treatments has enabled remarkable progress in the tissue and organ transplantation field by helping to prevent acute graft rejection. However, complications related to transplantation, such as infection by bacteria and viruses, and the occurrence of cancers resulting from prolonged immune suppression are major obstacles to overcome. Therefore, transplantation immunology research efforts should focus on the induction of donor-specific immune tolerance which preserves patient immune competence which promotes infection and cancer surveillance. Additionally, lifelong administration of immunosuppressants should be forgone in preference to short term therapies. In the 1990s, Dr. Shimon Sakaguchi identified the CD4⁺CD25⁺ regulatory T cells which develop in the thymus, and demonstrated that these cells play crucial roles in the maintenance of immune self tolerance. Studies which followed proved that these regulatory T cells are important to the control of autoimmune disease and prevention of graft rejection. Regulatory T cells have also been found to induce immune tolerance in rodent models. In this review, we discuss several considerations for the use of regulatory T cell therapy in the clinical transplantation field.

Keywords: Transplantation, Immune tolerance, Regulatory T lymphocytes

Figures and Tables

Fig. 1

Linked suppression and infectious tolerance. Linked suppression of naive T cells responding to antigen 2 (Ag2) can occur when the antigen-presenting cell (APC) is simultaneously also presenting a different antigen (Ag1) to regulatory T cells (Tregs). The Treg can then act to inhibit the full activation of the naive T cell, either because the naive T cell is brought within the range of close acting cytokines or cell surface ligands of the Treg or because the Treg can modify the status of the APC. One way in which Treg cells may modulate APC activity towards anti-inflammatory presentation is to produce transforming growth factor β (TGFβ). In some cases, the naive T cell may receive sufficiently tolerogenic signals from the Treg and/or APC that it is itself converted to a Treg cell. This second cohort of Tregs then confers infectious tolerance against Ag2. Reprinted from Fig. 1 of reference [86].

Fig. 2

Plasticity of CD4⁺ T Cells. Recent findings suggest that T helper cell differentiation is more plastic than previously appreciated. Each CD4⁺ T cell subset can adopt alternate cytokine profiles in response to cytokine environmental changes. Among four subsets of T cells, Treg cells and Th17 cells display the highest propensity to switch to other phenotypes. The molecular mechanism underlying this plasticity may be related to poised, bivalent epigenetic states (i.e., permissive H3K4me3 plus repressive H3K27me3 marks) at the transcriptional regulator (e.g., T-bet and Gata3) gene loci. Consistent with permissive epigenetic marks at Foxp3 and RORγt gene loci, coexpression of Foxp3 and RORγt occurs in Treg cells, but RORγt activity is inhibited by Foxp3. Reprinted from Fig. 2 of reference [49].

Table 1

Subsets of natural and induced regulatory T cells^a

^aSubsets have been detected in humans and rodents. ^bIssue uncertain, not yet clear or not yet investigated.

Abbreviations: APC, antigen-presenting cell; DC, dendritic cell; ILT, immunoglobulin transcript; NKTreg, regulatory cell of natural killer T cell phenotype; Th3, T helper type 3; Tr1 cell, type 1 regulatory T cell; Treg, regulatory T cell.

Reprined from Table 1 of reference [85].

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