Mucosal associated invariant T (MAIT) cells recognise conserved microbial metabolites from riboflavin synthesis. Striking evolutionary conservation and pulmonary abundance implicate them in antibacterial host defence, yet their functions in protection against clinically important pathogens are unknown. Here we show that mouse Legionella
longbeachae infection induces MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells associated with immune protection detectable in immunocompetent host animals. MAIT cell protection is more evident in mice lacking CD4+ cells, and adoptive transfer of MAIT cells rescues immunodeficient Rag2−/−γC−/− mice from lethal Legionella infection. Protection is dependent on MR1, IFN-γ and GM-CSF, but not IL-17A, TNF or perforin, and enhanced protection is detected earlier after infection of mice antigen-primed to boost MAIT cell numbers before infection. Our findings define a function for MAIT cells in protection against a major human pathogen and indicate a potential role for vaccination to enhance MAIT cell immunity.
T cell receptors (TCRs) recognize antigens presented by major histocompatibility complex (MHC) and MHC class I–like molecules. We describe a diverse population of human γδ T cells isolated from peripheral blood and tissues that exhibit autoreactivity to the monomorphic MHC-related protein 1 (MR1). The crystal structure of a γδTCR–MR1–antigen complex starkly contrasts with all other TCR–MHC and TCR–MHC-I-like complex structures. Namely, the γδTCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 α3 domain. A similar pattern of reactivity was observed for diverse MR1-restricted γδTCRs from multiple individuals. Accordingly, we simultaneously report MR1 as a ligand for human γδ T cells and redefine the parameters for TCR recognition.
The antigen-presenting molecule MR1 (MHC class I-related protein 1) presents metabolite antigens derived from microbial vitamin B2 synthesis to activate mucosal-associated invariant T (MAIT) cells. Key aspects of this evolutionarily conserved pathway remain uncharacterized, including where MR1 acquires ligands and what accessory proteins assist ligand binding. We answer these questions by using a fluorophore-labeled stable MR1 antigen analog, a conformation-specific MR1 mAb, proteomic analysis, and a genome-wide CRISPR/Cas9 library screen. We show that the endoplasmic reticulum (ER) contains a pool of two unliganded MR1 conformers stabilized via interactions with chaperones tapasin and tapasin-related protein. This pool is the primary source of MR1 molecules for the presentation of exogenous metabolite antigens to MAIT cells. Deletion of these chaperones reduces the ER-resident MR1 pool and hampers antigen presentation and MAIT cell activation. The MR1 antigen-presentation pathway thus co-opts ER chaperones to fulfill its unique ability to present exogenous metabolite antigens captured within the ER.
Liver glycogen, a highly branched polymer of glucose, is important for maintaining blood-glucose homeostasis. It was recently shown that db/db mice, a model for Type 2 diabetes, are unable to form the large composite glycogen α particles present in normal, healthy mice. In this study, the structure of healthy mouse-liver glycogen over the diurnal cycle was characterized using size exclusion chromatography and transmission electron microscopy. Glycogen was found to be formed as smaller β particles, and then only assembled into large α particles, with a broad size distribution, significantly after the time when glycogen content had reached a maximum. This pathway, missing in diabetic animals, is likely to give optimal blood-glucose control during the daily feeding cycle. Lack of this control may contribute to, or result from, diabetes. This discovery suggests novel approaches to diabetes management.
Al
distributions and locations of corresponding nonframework cations
in SSZ-13 zeolites have significant impact on their catalytic and
adsorption properties. Herein, we demonstrate the feasibility of elucidating
Na+ locations and correlated Al distributions in a series
of Na-SSZ-13 zeolites with Si/Al ratios ranging from 4 to 48 by combining 23Na MQ MAS NMR spectroscopy and DFT calculations. As only
one crystallographically inequivalent T site exists in CHA cages,
the isolated Al and the Al pair (Al–O–Si–O–Si–O–Al)
and (Al–O–Si–O–Al) in 6-membered ring
(MR) distributions and the corresponding Na+ locations
are clearly discriminated. In the high-silica Na-SSZ-13 zeolite, Na+ ions are mainly located at the 6-MR SIIa0 site corresponding
to one Al substitution in the CHA cage. However, a small amount of
the Al pair in 6-MR is still observable even with an Si/Al ratio of
48, corresponding to two Na+ ions located at 6-MR SIIa1
and 8-MR SIII’a1 sites, respectively. With more Al substitutions
in the CHA cage, a portion of Na+ ions with high mobility
among different SII sites may result in the SIII’b site. In
Al-rich SSZ-13 zeolite (Si/Al = 4), the presence of Si(2Al) and Si(3Al)
may lead to Na+ being located at 6-MR SIIa2, with 23Na NMR signals exhibiting relatively large quadrupolar interactions,
and at 8-MR SIII’a2, with NMR signals overlapped with that
of the SIII’a1 site. This approach may expand its application
in discrimination of Al distributions in other zeolites to gain deeper
understanding of the relationship between the structure and the property
for their applications in catalysis and adsorption.
Glycogen, a hyperbranched glucose polymer, is the blood-sugar reservoir in animals. Liver glycogen comprises small β particles, which can join together as large composite α particles. It had been shown that the binding between β in α particles in the liver of diabetic mice is more fragile than in healthy mice. This could be linked to the loss of blood-sugar control characteristic of diabetes if the rate per monomer unit of the enzymatic degradation to glucose of α particles were significantly slower than that of β particles. This is tested here by examining the in vitro time evolution of the molecular size distribution of glycogen from the livers of healthy rats and diabetic mice, containing distinct components of both α and β page 2 particles; this treatment is analogous to the "competitive growth" method used to explore mechanisms in emulsion polymerization. Simulations for the time evolution of the molecular size distribution were also performed. It is found that the degradation rate per monomer unit is indeed faster for the smaller particles, supporting the hypothesis of a causal link between chemical fragility of glycogen from diabetic liver with poor control of blood-sugar release. Comparison between simulations and experiment indicate that α and β particles have significant structural differences.
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