The Role of Mucosal Associated Invariant T Cells in Antimicrobial Immunity

Abstract

Mucosal associated invariant T (MAIT) cells are an innate-like T cell subset prevalent in humans and distributed throughout the blood and mucosal sites. Human MAIT cells are defined by the expression of the semi-invariant TCRα chain TRAV1-2/TRAJ12/20/33 and are restricted by the non-polymorphic major histocompatibility complex (MHC) class I-like molecule, MHC-related protein 1, MR1. MAIT cells are activated by small organic molecules, derived from the riboflavin biosynthesis pathway of bacteria and fungi, presented by MR1. Traditionally, MAIT cells were thought to recognize a limited number of antigens due to usage of an invariant TCRα chain and restriction by a non-polymorphic MHC molecule. However, recent studies demonstrate that the TCR repertoire of MAIT cells is more heterogeneous, suggesting there is a more diverse array of MR1 antigens that MAIT cells can recognize. In response to infected cells, MAIT cells produce the pro-inflammatory cytokines, IFN-γ and TNF, and are cytolytic. Studies performed in MR1-deficient mice suggest that MAIT cells can provide anti-bacterial control within the first few days post-infection, as well as contribute to enhanced adaptive immunity in murine models of respiratory infections. In humans, the role of MAIT cells is unclear; however, evidence points to interplay between MAIT cells and microbial infections, including Mycobacterium tuberculosis. Given that MAIT cells are pro-inflammatory, serve in early control of bacterial infections, and appear enriched at tissue sites where microbes interface and gain access to the body, we postulate that they play an important role in antimicrobial immune responses. In this review, we discuss the most recent studies on the function and phenotype of MAIT cells, including their TCR diversity and antigenic repertoire, with a focus on the contribution of human MAIT cells in the immune response to microbial infection.

Keywords: MR1; antimicrobial; immunity; mucosal associated invariant T cells.

Figures

Figure 1

Molecular basis of antigen presentation by MR1 and recognition by MAIT TCRs. (A) Backbone (ribbon) and surface representations of the structure of human MR1 (PDB ID: 4GUP) are shown in cyan. In the MR1, A′ pocket is shown the 6-FP ligand in yellow, with nitrogen atoms colored blue, and oxygen in red. The A′ and F′ pockets are labeled as such. (B) MAIT TCR recognition of MR1 presenting the stimulatory antigen, rRL (rRL-6-CH2OH) (PDB ID: 4LCC), only CDR loops of the MAIT TCR are shown, positioned in complex with MR1. CDRa loops are colored pink; CDRb are shown in blue. The rRL antigen is shown as above for 6-FP. In the insert is a zoomed view of the CDR3a (Y95) and CDR3b (E99) loop interactions with the ribtyl chain of rRL, showing the hydrogen-bonds as yellow dashes.

Figure 2

Possible mechanisms of MAIT cells in human antibacterial immunity. MAIT cells with effector function egress from the thymus and circulate through the blood and lymph as well as traffic to mucosal tissues, including the lungs. Upon bacterial infection, a dendritic cell (or other MR1-expressing cell) can activate MAIT cells by presentation of bacterial-derived antigens on MR1 (MR1-Ag) to the MAIT TCR (TRAV1-2). MAIT cells activated in an MR1-dependent manner may then (i) undergo clonal expansion of antigen-specific MAIT cells in the lungs and thus aquire long-term memory to specific pathogens, a hypothesis that still needs to be tested. (ii) directly lyse cells infected with Mtb by secreting the cytotoxic molecules granzyme and perforin (22, 25, 44), (iii) indirectly kill mycobacteria by secreting the pro-inflammatory cytokines, TNF and IFN-γ, through recruitment and activation of effector cells to the site of infection. MAIT cells may also be activated, in an MR1-independent manner, by IL-12 produced by a local infected macrophage. The activated MAIT cell may then secrete IFN-γ and stimulate a positive feedback cycle in which IFN-γ augments expression of IL-12 by infected macrophages and vice versa. Furthermore, the abundance of IFN-γ may then contribute to priming and maturation of naïve DCs that traffic to the lymph node and initiate Th1 immunity. Thus, suggesting a possible scenario by which MAIT cells may bridge innate and adaptive immunity.