MAIT cells and viruses

Abstract

Mucosal associated invariant T cells (MAIT cells) bear a T cell receptor (TCR) that specifically targets microbially derived metabolites. Functionally, they respond to bacteria and yeasts, which possess the riboflavin pathway, essential for production of such metabolites and which are presented on MR1. Viruses cannot generate these ligands, so a priori, they should not be recognized by MAIT cells and indeed this is true when considering recognition through the TCR. However, MAIT cells are distinctive in another respect, since they respond quite sensitively to non-TCR signals, especially in the form of inflammatory cytokines. Thus, a number of groups have shown that virus infection can be "sensed" by MAIT cells and a functional response invoked. Since MAIT cells are abundant in humans, especially in tissues such as the liver, the question has arisen as to whether this TCR-independent MAIT cell triggering by viruses plays any role in vivo. In this review, we will discuss the evidence for this phenomenon and some common features which emerge across different recent studies in this area.

Keywords: TLR; MAIT cells; MR1; cytokines; virus.

Figure 1

Activation of MAIT cells in a TCR‐dependent versus TCR‐independent manner. The left‐hand side shows activation following bacterial stimulation in the case of a bacterial species which has the riboflavin operon active and can produce the ligand—these may be cytosolic or taken up into phagosomes in a professional antigen‐presenting cell. Recognition occurs via TCR through recognition of ligand‐MR1 complexes, accompanied by cell surface signals (such as CD28/CD80 interactions) and cytokines. The balance between MR1‐dependent and ‐independent signals may vary over time, even if ligand is produced. The right‐hand side shows the situation in response to viruses, where ligand is not present, but cytokines will be produced through triggering of toll‐like receptors (TLRs) or other pattern recognition receptors (PRRs) which also lead to inflammasome activation. The role of coreceptor stimulation in this setting is unknown. In both cases, granzyme B activation is seen, although whether this can lead to degranulation in the setting of virus infection is not known.

Figure 2

A cartoon illustrating the activation of MAIT cells by viruses. Viruses signal via PRRs to stimulate the production of cytokines. Other signals may also be involved. The exact blend of cytokines involved and the kinetics of their release varies between individual viruses and also between different APCs. Cytokines may activate MAIT cells directly via their cytokine receptors (e.g. IL‐12 and IL‐18) or indirectly through stimulating the release of other cytokines (e.g. IL‐15). Cytokine‐activated MAIT cells may have antiviral functions (possibly including cytotoxicity, although that is yet to be demonstrated), enhance inflammation and proliferate. In chronic viral infections, cytokine‐activated MAIT cells may also undergo activation‐induced cell death.