Preferential recognition of a microbial metabolite by human V 2V 2 T cells
Kia Joo PuanJin ChenH. WangGhanashyam SarikondaAmy M. RakerH. K. LeeMegan I. SamuelsonE. Märker‐HermannLjiljana Paša‐TolićE. NievesJosé‐Luis GinerTomohisa KuzuyamaCraig T. Morita
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Human Vγ2Vδ2 T cells are stimulated by prenyl pyrophosphates, such as isopentenyl pyrophosphate (IPP), and play important roles in mediating immunity against microbial pathogens and have potent anti-tumor activity. (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) has been identified as a metabolite in the 2-C-methyl-D-erythritol-4 phosphate (MEP) pathway for isoprenoid biosynthesis that is used by many bacteria and protozoan parasites. We find that HMBPP is the major Vγ2Vδ2 T-cell antigen for many bacteria, including Mycobacterium tuberculosis, Yersinia enterocolitica and Escherichia coli. HMBPP was a 30 000-fold more potent antigen than IPP. Using mutant bacteria, we show that bacterial antigen levels for Vγ2Vδ2 T cells are controlled by MEP pathway enzymes and find no evidence for the production of 3-formyl-1-butyl pyrophosphate. Moreover, HMBPP reactivity required only germ line-encoded Vγ2Vδ2 TCR elements and is present at birth. Importantly, we show that bacterial HMBPP levels correlated with their ability to expand Vγ2Vδ2 T cells in vivo upon engraftment into severe combined immunodeficiency–beige mice. Thus, the production of HMBPP by a microbial-specific isoprenoid pathway plays a major role in determining whether bacteria will stimulate Vγ2Vδ2 T cells in vivo. This preferential stimulation by a common microbial isoprenoid metabolite allows Vγ2Vδ2 T cells to respond to a broad array of pathogens using this pathway.Keywords:
Isopentenyl pyrophosphate
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Cell-free systems were prepared from fresh, cut and black rot-diseased tissues of sweet potato roots. When incubated in the presence of mevalonate, all these systems were capable of synthesizing 5-phosphomevalonate, mevalonate-5-pyrophosphate and isopentenyl pyrophosphate. The time courses for the appearance of the 14C-labeled metabolites suggested the following order of synthesis: mevalonate → 5-phosphomevalonate → mevalonate-5-pyrophosphate → isopentenyl pyrophosphate. It was also shown; on prolonged incubation, that isopentenyl pyrophosphate was converted slowly to isopentenyl monophosphate. The activity for synthesis of isopentenyl pyrophosphate from mevalonate was higher in diseased tissue than in cut and healthy tissues.
Isopentenyl pyrophosphate
Farnesyl pyrophosphate
Mevalonate pathway
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The metabolism of zetidoline, a new neuroleptic, in the rat and the dog has been studied. From the urine of rats and dogs given 5 mg/kg of [2-14C] zetidoline orally, unchanged drug and five metabolites were isolated and the structures of four of them assigned by physicochemical analysis. They are: metabolite B, 4'-hydroxy-3'-chlorophenyl zetidoline; metabolite D, zetidoline without the aryl group; metabolite E, the 6'-hydroxy-4'-beta-D-glucuronide of metabolite B, and metabolite F, the 4'-beta-D-glucuronide of metabolite B. The plasma levels of zetidoline and its metabolites after iv administration show that the drug is rapidly excreted and/or metabolized in both animal species. The plasma radioactivity in the dog consists mainly of the pharmacologically active (neuroleptic) metabolite B, whereas in the rat it consists of the more polar metabolites. After oral administration, elimination in both species occurs mostly via the kidneys. In the dog, within a 24-hr period, 6.2 +/- 0.4% of the dose is accounted for as unchanged zetidoline, 7.6 +/- 0.5% as metabolite B, 10.1 +/- 0.7% as the unidentified metabolite C, and 21.4 +/- 1.1% as metabolite F. In the rat, over the same period, zetidoline is present in traces, metabolite B accounts for 6.9 +/- 0.3% of the dose, metabolite D for 6.6 +/- 0.9%, metabolite E for 15.2 +/- 1.4%, and metabolite F for 31.7 +/- 2.2%.
Glucuronide
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Isopentenyl pyrophosphate
Hevea
Farnesyl pyrophosphate
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Isopentenyl pyrophosphate
Farnesyl pyrophosphate
Geranylgeranyl pyrophosphate
Isoprene
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Isopentenyl pyrophosphate
Mevalonic acid
Squalene
Hevea
Isoprene
Nerolidol
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In order to assess the contribution of an active metabolite to the overall pharmacological response following drug administration it is necessary to characterise the metabolite concentration-time profile. The influence of route of drug administration on metabolite kinetics has been investigated by computer simulation. Comparisons between simulated profiles and published concentration-time data have been carried out. A route dependence in metabolite concentration-time curves is readily apparent provided the metabolite kinetics are formation rate limited and the hepatic clearance of drug is greater than 25 l/h (medium to highly cleared). Oral drug administration produces a triphasic metabolite concentration-time profile whereas only two phases are discernable after intravenous drug administration. The magnitude of the difference in maximum metabolite concentration is directly proportional to the hepatic clearance of drug due to first-pass metabolite production. The route dependence in the shape of the metabolite concentration-time curves is most dramatic when the absorption and distribution of drug and the elimination of metabolite is rapid. A reduction in the rate of either of these processes alters the shape of the metabolite concentration-time profile such that the consequence of first-pass metabolite formation may be reduced.
Active metabolite
Clearance
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Active metabolite
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1. The biotransformation of prostaglandin E(1) (PGE(1)) was studied in the isolated, perfused dog kidneys.2. An average 43% of PGE(1) was converted into the less polar metabolite I by a single passage through the kidney. As the re-circulation of the perfusate continued, PGE(1) was converted not only into metabolite I but also the least polar metabolite II. The velocity of the conversion of PGE(1) into metabolite I was significantly greater than that into metabolite II. Usually, six passages elapsed before maximum degradation of PGE(1) occurred.3. Further separation with silicic acid column chromatography and gas-liquid chromatography showed that metabolite II consists of two individual metabolites, metabolite IIa and metabolite IIb.4. The present study indicates that the kidney biotransforms PGE(1) rather rapidly into three metabolites which are less polar than PGE(1).
Dinoprostone
Primary metabolite
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