How regulatory T cells work

Top Cited Papers
Publisher Website
Google Scholar
Abstract
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.