Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target - PubMed (original) (raw)

Review

Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target

Dorothy K Sojka et al. Immunology. 2008 May.

Abstract

Naturally-occurring regulatory T cells (Tregs) are emerging as key regulators of immune responses to self-tissues and infectious agents. Insight has been gained into the cell types and the cellular events that are regulated by Tregs. Indeed, Tregs have been implicated in the control of initial activation events, proliferation, differentiation and effector function. However, the mechanisms by which Tregs disable their cellular targets are not well understood. Here we review recent advances in the identification of distinct mechanisms of Treg action and of signals that enable cellular targets to escape regulation. Roles for inhibitory cytokines, cytotoxic molecules, modulators of cAMP and cytokine competition have all been demonstrated. The growing number of inhibitory mechanisms ascribed to Tregs suggests that Tregs take a multi-pronged approach to immune regulation. It is likely that the relative importance of each inhibitory mechanism is context dependent and modulated by the inflammatory milieu and the magnitude of the immune response. In addition, the target cell may be differentially susceptible or resistant to distinct Treg mechanisms depending on their activation or functional status at the time of the Treg encounter. Understanding when and where each suppressive tool is most effective will help to fine tune therapeutic strategies to promote or constrain specific arms of Treg suppression.

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Figures

Figure 1

Figure 1

Regulatory T cells (Tregs) inhibit multiple stages of target cell activity. (a) Tregs appear to be unable to inhibit the early activation events (up-regulation of CD25 and CD69) of the first 6–10 hr of target CD4**+** T-cell activation. (b) Tregs suppress proliferation of multiple immune cell types possibly via attenuation of interleukin-2 production. (c) Suppression of CD4**+** T-cell differentiation by limiting the duration of T-cell receptor signalling or inhibiting the induction of the lineage specific transcription factors GATA3 and Tbet. (d) Treg suppression of effector T-cell cytokine production (interferon-γ and interleukin-4 by T helper type 1 and type 2 cells, respectively); inhibition of lytic granule release by CD8 effectors; inhibition of B-cell antibody production, directly or via blockade of CD4 help.

Figure 2

Figure 2

Mechanisms of regulatory T-cell (Treg) suppression. (a) Cell–cell contact. Tregs may suppress target cells via direct interaction of receptor–ligand pairs on Tregs and target cells; delivery of suppressive factors via gap junctions including cyclic adenosine monophosphate (cAMP); direct cytolysis; membrane-bound suppressive cytokines such as transforming growth factor-β (TGF-β); and/or indirectly via modulating the antigen-presenting cell (APC) through cell–cell contact, possibly through reverse signalling via Treg–cytotoxic T-lymphocyte antigen-4 (CTLA-4) engagement of B7 on dendritic cells. (b) Soluble suppressive factors. Tregs can directly secrete interleukin-10 (IL-10), TGF-β and IL-35 or induce APCs to secrete such factors. Expression of CD73/CD39 by Tregs facilitates the local generation of adenosine that can down-modulate immune function. (c) Competition. Tregs may compete for some cytokines that signal via receptors that contain the common γ-chain (IL-2, IL-4 and IL-7). Additionally they may compete for APC costimulation via constitutive expression of CTLA-4. Red arrow indicates an inhibitory signal.

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