Regulatory T (TReg) cells are essential for maintaining peripheral tolerance, preventing autoimmunity and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting anti-tumour immunity.
TReg cells have multiple mechanisms at their disposal to mediate their suppressive effects. These can be grouped into four basic 'modes of action': suppression by inhibitory cytokines, suppression by cytolysis, suppression by metabolic disruption and suppression by modulation of dendritic-cell (DC) maturation or function.
Suppression by inhibitory cytokines: interleukin-10 (IL-10), transforming growth factor-β (TGFβ) and the newly identified IL-35 are key mediators of TReg-cell function. Although they are all inhibitory, the extent to which they are used in distinct pathogenic or homeostatic settings differs, suggesting a non-overlapping function.
Suppression by cytolysis: both mouse and human TReg cells have been shown to mediate cytolysis via granzyme A and/or granzyme B and perforin in vitro and in vivo.
Suppression by metabolic disruption: a collection of intriguing mechanisms have recently been shown to either suppress or kill the target cell. Cytokine-deprivation-mediated apoptosis is mediated by the rapid consumption of IL-2 by CD25+ TReg cells, whereas the pericellular generation of adenosine and the intracellular transfer of cyclic AMP through membrane gap junctions expose the target cell to two potently inhibitory molecules.
Suppression by modulation of DC maturation or function: two mechanisms have been proposed. First, cytotoxic T-lymphocyte antigen 4 (CTLA4)–CD80/CD86 interactions induce the release of indoleamine 2,3-dioxygenase (IDO), a potent regulatory molecule, which induces the catabolism of tryptophan into pro-apoptotic metabolites. Second, lymphocyte-activation gene 3 (LAG3) binding to MHC class II molecules inhibits DC maturation and function.
Several complicating issues should be considered when evaluating the importance of these varied mechanisms. First, TReg-cell function is considered contact-dependent yet it is not clear how some mechanisms might mediate their function in this manner (for example, cytokines). Second, it is not clear for many of these mechanisms whether the primary target cell is the effector T cells and/or DCs or other antigen-presenting cells.
An important question is how many mechanisms do TReg cells need. There could be a single primary mechanism, multiple redundant mechanisms or multiple non-redundant mechanisms. Current data favour the latter but this remains to be fully defined and may vary depending on type of TReg cell involved and the context in which it is mediating its regulatory function.
We present the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate TReg-cell function.
Regulatory T (TReg) 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 TReg 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 TReg cells to mediate suppression and discuss whether one or many of these mechanisms are likely to be crucial for TReg-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 TReg-cell function.
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We thank Randolph Noelle and Peter Ernst for granting permission to cite their unpublished observations. This work is supported by the US National Institutes of Health (NIH), the Juvenile Diabetes Research Foundation (JDRF), a Cancer Center Support CORE grant and the American Lebanese Syrian Associated Charities (ALSAC). We apologize to those authors whose work we could not cite due to space limitations.
- Peripheral tolerance
The lack of self-responsiveness of mature lymphocytes in the periphery to specific antigens. These mechanisms control potentially self-reactive lymphocytes that have escaped central-tolerance mechanisms. Peripheral tolerance is associated with suppression of the production of self-reactive antibodies by B cells and inhibition of self-reactive effector T cells, such as cytotoxic T lymphocytes. The actions of regulatory T cells constitute one mechanism of peripheral tolerance.
- Type 1 diabetes
A chronic autoimmune disease that is characterized by the T-cell-mediated destruction of β-cells (which secrete insulin) in the pancreas. Individuals with type 1 diabetes develop hyperglycaemia and can develop diabetes-associated complications in multiple organ systems owing to a lack of insulin.
- Inflammatory bowel disease
(IBD). A T-cell-mediated inflammatory response that affects the gastrointestinal tract. There are two forms of IBD in humans; Crohn's disease, which can affect any part of the gastrointestinal tract but usually descends from the terminal ileum, and ulcerative colitis, which mainly affects the colon. In the mouse model of IBD, most of the inflammation is confined to the large intestine. The target antigen for the pathogenic T cells is unknown.
- Sterilizing immunity
An immune response that leads to the complete removal of the pathogen.
- Airway hyper-reactivity
Initiated by exposure to a defined stimulus that is usually tolerated by normal individuals and that causes broncho-constriction and airway infiltration of inflammatory cells in allergic individuals.
- Experimental autoimmune encephalomyelitis
(EAE). An animal model of the human autoimmune disease multiple sclerosis. EAE is experimentally induced in animals by immunization with myelin or with peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.
Small, lipid-bilayer vesicles that are released from activated cells. They comprise either plasma membrane or membrane derived from intracellular vesicles.
A transmembrane receptor involved in the pathway for direct cell–cell signalling that regulates cell-fate choice in the development of many cell lineages, and therefore is vital in the regulation of embryonic differentiation and development.
A family of serine proteases that are found primarily in the cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells. They enter target cells through perforin pores, and cleave and activate intracellular caspases, resulting in target-cell apoptosis.
A component of cytolytic granules that participates in the permeabilization of plasma membranes, allowing granzymes and other cytotoxic components to enter target cells.
- Adenosine nucleosides
Adenosine (C10H13N5O4) is a ribonucleoside (adenine linked to ribose) that is a structural component of nucleic acids. It is also the primary molecular component of cyclic AMP (an important intracellular second messenger), AMP, ADP and ATP (a key sourse of chemical energy for many enzymatic reactions).
Enzymes that are outside the cell membrane and therefore can cleave extracellular substrates. These are typically tethered to the outside of the cell by a transmembrane domain.
- TH17 cells
(T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-6, IL-21 and IL-23, as well as the transcription factors RORγt (retinoic-acid-receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).
- Intravital microscopy
This is used for examination of biological processes, such as leukocyte–endothelial-cell interactions, in living tissue. In general, translucent tissues are used, such as the mesentery or cremaster muscle, which can be exposed and mounted for microscopic observation.
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Vignali, D., Collison, L. & Workman, C. How regulatory T cells work. Nat Rev Immunol 8, 523–532 (2008). https://doi.org/10.1038/nri2343
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