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Review
, 3 (6)

Regulatory Cells and Transplantation Tolerance

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Review

Regulatory Cells and Transplantation Tolerance

Stephen P Cobbold et al. Cold Spring Harb Perspect Med.

Abstract

Transplantation tolerance is a continuing therapeutic goal, and it is now clear that a subpopulation of T cells with regulatory activity (Treg) that express the transcription factor foxp3 are crucial to this aspiration. Although reprogramming of the immune system to donor-specific transplantation tolerance can be readily achieved in adult mouse models, it has yet to be successfully translated in human clinical practice. This requires that we understand the fundamental mechanisms by which donor antigen-specific Treg are induced and function to maintain tolerance, so that we can target therapies to enhance rather than impede these regulatory processes. Our current understanding is that Treg act via numerous molecular mechanisms, and critical underlying components such as mTOR inhibition, are only now emerging.

Figures

Figure 1.
Figure 1.
Regulation of the foxp3 locus. The genomic organization of the foxp3 locus is depicted (not to scale) with the position of the most important regulatory elements shown, together with the positive and negative regulatory transcription factors that have been shown to bind to them and the primary function of each element.
Figure 2.
Figure 2.
Treg cells act within tissue to create a state of induced immune privilege. A localized tolerogenic microenvironment is established in tolerated tissues by the interaction of foxp3+ Treg cells with cells capable of presenting antigen in the context of MHC-II. These MHC-II+-presenting cells, including dendritic cells (modulated to “TolDC”), macrophages (modulated to Type 2 Mϕ), and mast cells both contribute to, and are modulated by, this tolerogenic microenvironment, which is maintained by the cytokines TGF-β, IL10, and IL-35, the CD39- and CD73-mediated conversion of ATP to adenosine, and the expression of multiple enzymes that deplete essential amino acids (EAAs). In addition, Treg cells may down-regulate antigen presentation by CTLA4-mediated trogocytosis of the costimulatory B7 ligands, or by granzyme-mediated killing of inflammatory/donor APCs. In this tolerogenic microenvironment, effector T cells may be “reprogrammed” to differentiate into Treg cells expressing foxp3 and/or IL-10 in a form of infectious tolerance.

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