This presentation will address our broad understanding of MAIT cell biology and the potential for T cell reactivity of non-MAIT cells to different MR1-Ag complexes.
Mucosal-associated invariant T cells (MAIT cells) are emerging as important T cells in a variety of contexts, including protective immunity to pathogens (bacteria, fungi, parasites and viruses); hastening wound healing and tissue repair; and modulation of tumour immunity, autoimmunity and graft versus host disease. MR1-deficient mice have no unprovoked ‘phenotype’ and in healthy immune competent mice, protective immunity provided by MAIT cells appears largely redundant, but critical in immunodeficient mice. This poses the question of what functions throughout evolution have selected for the high level of MAIT cell-MR1 conservation across species.
MAIT cells are part of a family of non-classical T cells but are distinguished by their relevant abundance and polyfunctional phenotypic properties, including cytotoxicity and diverse cytokine production. MAIT cells develop in the thymus, selected on double positive thymocytes in a multi-step pathway. Some evidence suggests their thymic selection is by microbial ligands, but other evidence suggests some might be selected on classical MHC molecules. They emerge from the thymus mostly pre-programmed, migrating to organ sites, particularly the lung and liver but all organs, including lymphoid tissue. MAIT cells have innate-like qualities with long lived tissue residency and rapid activation properties. They are activated in a context-dependent way by both hemopoietic and non-hemopoietic Ag presenting cells and their expansion is dependent upon co-stimuli. Mouse MAIT cells are more polarised (MAIT 1 and MAIT 17) in their cytokine profiles than human MAIT cells. MAIT cells express an evolutionarily conserved, semi-invariant TCR composed of an oligoclonal TCR chain TRAV1-2-TRAJ33, 12 or 20 in humans, mostly in combination with TBV6 or TRBV20. Increasing TCR receptor diversity has been identified through deep sequencing experiments for which a physiological role is yet to be attributed. Most human MAIT cells are CD8+ and this co-receptor binds the a3 domain of MR1 enhancing Ag-recognition and supporting a low level of self-reactivity.
MR1 binds the dominant activating MAIT cell ligands, 5-OP-RU (5‐(2‐oxopropylideneamino)‐6‐D‐ribitylaminouracil) and 5-OE-RU (5‐(2‐oxoethylideneamino)‐6‐D‐ribitylaminouracil) derived as transitory intermediates from microbial riboflavin synthesis. These Ags load MR1 in the ER, triggering a conformational change that leads to egress to the plasma membrane. They bind in an aromatic cradle within the A’-pocket of MR1 the cleft of which is tantalisingly large enough with a shallower F-pocket, to theoretically support binding to other ligands. It is now known that MR1 can bind certain drugs, purine and other adducts of the stress-related compound malondialdehyde, sulphated bile acids, ribityl lumazines, pterins, riboflavin catabolites and vitamers of pyridoxine (vitamin B6), the latter of which preferentially bind the MR1 allomorph, MR1*04. These ligands generally interact weakly with non-MAIT cells (referred to as ‘MR1T cells’ or ‘diverse MR1T cells’) and have phenotypic characteristics of conventional MHC class I restricted T cells as well as largely being CD8-dependent. The physiological relevance of MR1T cells remains to be proven but there is enthusiasm that they might be important in immunity, including tumour immunity.
The immunotherapeutic potential of MAIT/MR1T cells is now an area of considerable interest driven by their relative abundance and diverse antigen specificity respectively, coupled with their natural tissue tropism, their polyfunctionality and the relatively monomorphic nature of MR1.