Mucosal-associated-invariant-T (MAIT) cells are an innate-like T cell subset that recognizes microbial-derived vitamin B metabolites. In contrast to conventional T cells, MAIT cells have an antigen-experienced phenotype and express memory markers by default. When activated, MAIT cells rapidly produce copious amounts of cytokines, resembling IFNg+ Th1- or IL-17+ Th17 effectors cells. While memory-like vs effector-like states in conventional CD4 and CD8 T cells are controlled by mutually exclusive metabolic states, the question remains as to which metabolic programs MAIT cells adopt at steady-state and after infection. Here we integrate scRNA-seq analysis with single-cell metabolic characterization of MAIT cells from humans and mice. We discovered a memory-like metabolic program that is acquired in the thymus and at steady state in the periphery. We identify a novel cluster of circulatory MAIT cells which is metabolically similar to IFNg+ MAIT1-like cells and preferentially consumes glucose. MAIT17 clusters, most prevalent in mice, uniquely engage in fatty acid uptake and mitochondrial metabolism. Following exposure to bacteria, mouse MAIT cells expand as CD127−KLRG1+ and CD127+KLRG1− populations that adopt divergent transcriptomic and metabolic profiles with enhanced functionality. They remain altered long-term. CD127+, but not KLRG1+ MAIT cells engage in MAIT17-like metabolic and effector pathways and protect mice from lung infection with Streptococcus pneumoniae. In contrast, KLRG1+ MAIT cells depend on Hif1a-driven glycolysis and remain metabolically dormant but ready to respond, more rapidly engaging multiple metabolic programs to protect from viral infection. Supported by R01AI137230 (MK), R01AI71922 (MK), Wellcome Trust 210842_Z_18_Z (TR)
De novo combination of natural product (NP) fragments by means of efficient, complexity- and stereogenic character-generating transformations to yield pseudo-natural products (PNPs) may explore novel biologically relevant chemical space. Pyrrolidine-...
Although mucosal-associated invariant T (MAIT) cells provide rapid, innate-like responses, they are not pre-set, and memory-like responses have been described for MAIT cells following infections. The importance of metabolism for controlling these responses, however, is unknown. Here, following pulmonary immunization with a Salmonella vaccine strain, mouse MAIT cells expanded as separate CD127−Klrg1+ and CD127+Klrg1− antigen-adapted populations that differed in terms of their transcriptome, function and localization in lung tissue. These populations remained altered from steady state for months as stable, separate MAIT cell lineages with enhanced effector programmes and divergent metabolism. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic programme, which was critical for their maintenance and IL-17A synthesis. This programme was supported by high fatty acid uptake and mitochondrial oxidation and relied on highly polarized mitochondria and autophagy. After vaccination, CD127+ MAIT cells protected mice against Streptococcus pneumoniae infection. In contrast, Klrg1+ MAIT cells had dormant but ready-to-respond mitochondria and depended instead on Hif1a-driven glycolysis to survive and produce IFN-γ. They responded antigen independently and participated in protection from influenza virus. These metabolic dependencies may enable tuning of memory-like MAIT cell responses for vaccination and immunotherapies.
Selectively labelling of cells with damaged membranes is needed in contexts as simple as identifying dead cells in culture, or as complex as imaging membrane barrier functionality in vivo. The commonly used dyes are permanently coloured/fluorescent dyes that are simply excluded by intact membranes, but to achieve good image contrast therefore requires removing their extracellular signal by washing or background subtraction, which are not possible in vivo. Here, we develop fluorogenic probes which sensitively and selectively reveal damaged cells, without needing washing steps since their fluorescence turns on from near-zero background. From a set of novel fluorogenic probes impermeabilised by sulfonations along different vectors, we identify a specific disulfonated fluorogenic scaffold that enters cells only upon membrane damage, where it is enzymatically activated to mark them. The esterase probe iPS-FS2 is a reliable tool to reveal live cells that have been permeabilised by biological, biochemical, or physical membrane damage; and it can be used in multicolour microscopy. We confirm the modularity of this approach by also adapting it for redox-unmasked cell-excluded probes with improved hydrolytic stability. This scaffold-based design thus provides tools for wash-free in vivo imaging of membrane damage, which is relevant across many pathologies. The insights gained from these probes should also be translatable to damage-targeted prodrugs, for selective therapy of membrane-compromised cells.
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