title: Preferential recognition of a microbial metabolite by human Vgamma2Vdelta2 T cells.
abstract: Human Vgamma2Vdelta2 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 Vgamma2Vdelta2 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 Vgamma2Vdelta2 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 Vgamma2Vdelta2 TCR elements and is present at birth. Importantly, we show that bacterial HMBPP levels correlated with their ability to expand Vgamma2Vdelta2 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 Vgamma2Vdelta2 T cells in vivo. This preferential stimulation by a common microbial isoprenoid metabolite allows Vgamma2Vdelta2 T cells to respond to a broad array of pathogens using this pathway.
authors: Division of Rheumatology, Department of Internal Medicine and the Interdisciplinary Graduate Program in Immunology, University of Iowa College of Medicine, EMRB 400F, Iowa City, IA 52242, USA.
authors: Kia-Joo
authors: KJ
authors: Puan
authors: Chenggang
authors: C
authors: Jin
authors: Hong
authors: H
authors: Wang
authors: Ghanashyam
authors: G
authors: Sarikonda
authors: Amy M
authors: AM
authors: Raker
authors: Hoi K
authors: HK
authors: Lee
authors: Megan I
authors: MI
authors: Samuelson
authors: Elisabeth
authors: E
authors: Märker-Hermann
authors: Ljiljana
authors: L
authors: Pasa-Tolic
authors: Edward
authors: E
authors: Nieves
authors: José-Luis
authors: JL
authors: Giner
authors: Tomohisa
authors: T
authors: Kuzuyama
authors: Craig T
authors: CT
authors: Morita
mesh_terms: D000818:Animals; D011756:Diphosphates / Q000138:chemical synthesis / Q000276:immunology / Q000302:isolation & purification* / Q000378:metabolism*; D045782:Hemiterpenes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D023421:Models, Animal; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000737:chemistry / Q000276:immunology; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology
chemical_list: C443995:4-hydroxy-3-methylbut-2-enyl pyrophosphate; D011756:Diphosphates; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D011106:Polyisoprenyl Phosphates; D016692:Receptors, Antigen, T-Cell, gamma-delta; C004809:isopentenyl pyrophosphate