Trends in Immunology
ReviewHow MR1 Presents a Pathogen Metabolic Signature to Mucosal-Associated Invariant T (MAIT) Cells
Section snippets
MR1 Presents Derivatives of a Vitamin Building-Block Metabolite Conserved in Microbes
Multicellular organisms have evolved sophisticated mechanisms to fight infection by distinguishing self from foreign. The innate immune system uses multiple devices to directly recognize molecules that are fundamental ‘building blocks’ common to many pathogens −pathogen-associated molecular patterns (PAMPs) − allowing innate immune cells to respond rapidly to broad groups of organisms [1]. In contrast to this rapid and broadly specific system of pathogen detection, the adaptive immune system
A Short History of the Discovery of the MR1–MAIT Cell Ag Presentation Axis
The Mr1 gene was initially discovered in 1995 using a polymerase chain reaction-based strategy to amplify genes with sequence similarity to the α3 domain of MHC I [5]. Unlike MHC I, the Mr1 gene is monomorphic and located outside the MHC region. MR1 is highly conserved among species [6], particularly in the regions encoding the α1 and α2 domains, which form the Ag-binding site of classical MHC I and CD1 molecules. Not all MHC-like molecules have Ag-presenting functions, but this structural
The Road to MR1 Ag Discovery: Leads, Detours, and Success
The path to discovery of MR1 ligands opened with the realization that the ectodomain of MR1 could be secreted as a stable heterodimer with β2m only when expressed in cell-culture media supplemented with yeast extract and amino acids [10]. Without chaperones MHC I molecules are stable only when bound to peptide ligand [19], so it was inferred that a component of the culture medium was likely to bind to, and stabilize, MR1 in this experimental system. The same group showed that a
The MR1 Ag Presentation Pathway
The location where MR1 binds Ag, the intracellular trafficking route followed by the molecules before and after ligand binding, and the fate of the MR1–Ag complexes following exposure on the cell surface for MAIT cell recognition have been the subject of intense research that has sometimes yielded controversial results. Clarification of some of the discrepancies awaits further studies, but in the following sections we attempt to summarize the main conclusions in this area and speculate on
Concluding Remarks and Future Directions
The discovery that MR1 presents the broadly conserved family of VitBAgs has expanded the types of Ag that can be recognized by T cells. It has also allowed dissection of the intracellular events that characterize this novel Ag presentation pathway and opened an exciting new field with several important questions (see Outstanding Questions). There are discrepancies in the literature regarding the compartments where MR1 predominantly acquires its ligands, but this will probably be clarified with
Acknowledgments
The authors gratefully acknowledge support from the Australian Research Council (DECRA Fellowship, H.E.G.McW.; Discovery Project, J.A.V.), the National Health and Medical Research Council (Program Grant and Fellowship, J.A.V.), and the University of Melbourne (Early Career Researcher Grant, H.E.G.McW.).
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The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation
2022, Journal of Biological ChemistryCitation Excerpt :Although Spf1p has been shown to modulate ion concentrations in the ER, it has also been postulated that its substrates may be more diverse, potentially even including macromolecules such as aminophospholipids based on sequence similarities to P4-type ATPases (74, 111). Since it is still unclear how soluble MR1 ligands access the ER where they encounter partially folded, ligand-receptive MR1 molecules (37, 41) it is tempting to speculate that ATP13A1 may also transport vitamin metabolites, implying a role analogous to TAP, which transports antigenic peptides into the ER for loading onto MHC class I molecules (115). Pertinent to this, Sørensen and colleagues recently identified phosphatidyl-inositol 4-phosphate as a potent stimulator of Spf1p ATPase activity and hypothesized that the sterol flippase activity of P5A-ATPases may underlie the diverse phenotypes observed upon mutation of the transporters (114).
Why TAPBPR? Implications of an additional player in MHC class I peptide presentation
2021, Current Opinion in ImmunologyCitation Excerpt :Therefore, could TAPBPR have much broader functionality on a wider range of ligands than currently thought (Figure 1)? One such molecule containing an MHC fold is the non-classical MHC class I related protein MR1 which presents metabolites to mucosal associated invariant T cells [37]. The antigen processing pathway for MR1 has been largely unexplored.
MR1: a multi-faceted metabolite sensor for T cell activation
2020, Current Opinion in ImmunologyCitation Excerpt :Indeed, a small amount of MR1 is found on the surface of cell lines or primary cells in the absence of ligands [29]. To explain the origin of these molecules, we proposed that empty ER-resident MR1 is maintained in a folding equilibrium between a partially misfolded, predominant conformer that cannot leave the ER, and a minor one that can traffic to the cell surface [53]. However, we believe this cohort of MR1 molecules is unlikely to play a prominent role in Ag presentation because they represent a very small proportion compared to the ER-resident pool, and of these only a small number (∼5%) would be able to reach endosomes, escape transfer to lysosomes, and return to the cell surface bound to ligands.
MR1 antigen presentation to MAIT cells: new ligands, diverse pathways?
2018, Current Opinion in Immunology