How regulatory T cells work

Abstract

Regulatory T (T(Reg)) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumour immunity. Given that T(Reg) cells can have both beneficial and deleterious effects, there is considerable interest in determining their mechanisms of action. In this Review, we describe the basic mechanisms used by T(Reg) cells to mediate suppression and discuss whether one or many of these mechanisms are likely to be crucial for T(Reg)-cell function. In addition, we propose the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate T(Reg)-cell function.

Figure 1. Basic mechanisms used by T_reg cells

This schematic depicts the various regulatory T (T_reg)-cell mechanisms arranged into four groups centred around four basic modes of action. ‘Inhibitory cytokines’ include interleukin-10 (IL-10), interleukin-35 (IL-35) and transforming growth factor-β (TGF-β). ‘Cytolysis’ includes granzyme-A- and granzyme-B-dependent and perforin-dependent killing mechanisms. ‘Metabolic disruption’ includes high affinity IL-2 receptor α (CD25)-dependent cytokine-deprivation-mediated apoptosis, cyclic AMP (cAMP)-mediated inhibition, and CD39- and/or CD73-generated, adenosine–purinergic adenosine receptor (A2A)-mediated immunosuppression. ‘Targeting dendritic cells’ includes mechanisms that modulate DC maturation and/or function such as lymphocyte activation gene-3 (LAG3; also known as CD223)–MHC-class-II-mediated suppression of DC maturation, and cytotoxic T lymphocyte antigen-4 (CTLA4)–CD80/CD86-mediated induction of indoleamine 2,3-dioxygenase (IDO), which is an immunosuppressive molecule, by DCs.

Figure 2. Model for how effector T cells might boost T_reg-cell function

This occurs in three stages. (a) Initial regulatory T (T_reg)-cell activation induces production of regulatory factors such as interleukin-35 (IL-35). (b) T_reg cells ‘sense’ the presence of recently activated effector T cells through a receptor–ligand interaction (cell surface or soluble). (c) This in turn boosts or potentiates T_reg-cell function resulting in the enhanced production of regulatory mediators, such as IL-35, and perhaps the induction of new mediators.