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Preferential recognition of a microbial metabolite by human Vgamma2Vdelta2 T cells.
- Source :
-
International immunology [Int Immunol] 2007 May; Vol. 19 (5), pp. 657-73. Date of Electronic Publication: 2007 Apr 19. - Publication Year :
- 2007
-
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.
- Subjects :
- Animals
Diphosphates chemical synthesis
Diphosphates immunology
Hemiterpenes chemistry
Hemiterpenes metabolism
Humans
Lymphocyte Activation immunology
Mice
Models, Animal
Molecular Structure
Mycobacterium smegmatis chemistry
Mycobacterium smegmatis immunology
Organophosphorus Compounds chemistry
Organophosphorus Compounds metabolism
Polyisoprenyl Phosphates chemistry
Polyisoprenyl Phosphates immunology
Receptors, Antigen, T-Cell, gamma-delta immunology
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets microbiology
Diphosphates isolation & purification
Diphosphates metabolism
Polyisoprenyl Phosphates metabolism
Receptors, Antigen, T-Cell, gamma-delta metabolism
T-Lymphocyte Subsets metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0953-8178
- Volume :
- 19
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- International immunology
- Publication Type :
- Academic Journal
- Accession number :
- 17446209
- Full Text :
- https://doi.org/10.1093/intimm/dxm031