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. 2004;6(1):19-25.
doi: 10.1186/ar1037. Epub 2003 Dec 19.

A paragon of self-tolerance: CD25+CD4+ regulatory T cells and the control of immune responses

Zoltán Fehérvári  1 , Shimon Sakaguchi
Affiliations

A paragon of self-tolerance: CD25+CD4+ regulatory T cells and the control of immune responses

Zoltán Fehérvári et al. Arthritis Res Ther. 2004.

Abstract

The interest in naturally arising regulatory T (TR) cells as a paradigm for maintaining immunological self-tolerance has undergone an explosive re-emergence in recent years. This renaissance was triggered by several key experimental observations and the identification of specific molecular markers that have enabled the isolation and experimental manipulation of these cells. Although their existence was once controversial, a large body of evidence now highlights the critical roles of TR cells in maintaining immunological self-tolerance. Furthermore, abnormality of natural TR cells can be a primary cause of autoimmune and other inflammatory diseases in humans.

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Figures

Figure 1
Figure 1
A putative scheme for the development of regulatory T (TR) cells. TR and naïve conventional helper T cells (Th0) develop within a normal thymus through the processes of positive and negative selection. Precursor T cells of relatively high avidity trigger a TR cell developmental programme involving the activation of Foxp3, whereas T cell receptors of intermediate avidity yield Th0 cells. Additionally, regulatory cells can be peripherally generated (for example, Tr1 cells) when activated under tolerogenic conditions (for example, with immature dendritic cells). As yet it is unclear whether de facto Foxp3+ TR cells can be generated in the periphery or whether the Tr1 cells produced from conventional Th0 cells are equivalent to naturally present TR cells. IL, interleukin; TE cell, effector T cell; TGF, transforming growth factor.
Figure 2
Figure 2
Possible mechanisms of regulatory T (TR) cell suppression. These mechanisms are not necessarily mutually exclusive, and potentially two or more might act in concert. (a) Antigen-presenting cell (APC)-activated TR cells transduce an unidentified active negative signal to nearby effector T (TE) cells located on the same APC or an adjacent one. (b) TR cells outcompete TE cells for stimulatory ligands on the APC surface by virtue of their high expression of adhesion molecules. (c) TR cells modulate the behaviour of the APC so that they become ineffective or suppressive stimulators of TE cells. (d) CD25 expression by the TR cells acts as an interleukin-2 sink and hinders the autocrine/paracrine stimulation of TE cells.
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