TY - JOUR
T1 - Preferential recognition of a microbial metabolite by human Vγ2Vδ2 T cells
AU - Puan, Kia Joo
AU - Jin, Chenggang
AU - Wang, Hong
AU - Sarikonda, Ghanashyam
AU - Raker, Amy M.
AU - Lee, Hoi K.
AU - Samuelson, Megan I.
AU - Märker-Hermann, Elisabeth
AU - Pasa-Tolic, Ljiljana
AU - Nieves, Edward
AU - Giner, José Luis
AU - Kuzuyama, Tomohisa
AU - Morita, Craig T.
N1 - Funding Information:
This work was supported in part by grants from the National Institute of Arthritis and Musculoskeletal and Skin Disease (RO1 AR45504), the National Institute of Allergy and Infectious Diseases (Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, U54 AI057160), the Arthritis Foundation and the Carver Research Foundation. We thank M. Curtiss and D. Colgan for critical review of the manuscript. The accurate mass measurements were performed at the W. R. Wiley Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the U.S. Department of Energy’s Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory. Pacific Northwest National Laboratory is operated for the Department of Energy by Battelle.
PY - 2007/5
Y1 - 2007/5
N2 - 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.
AB - 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.
KW - 2-C-methyl-D-erythritol-4 phosphate pathway
KW - Microbial immunity
KW - Prenyl pyrophosphate antigens
KW - γδ T cells
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U2 - 10.1093/intimm/dxm031
DO - 10.1093/intimm/dxm031
M3 - Article
C2 - 17446209
AN - SCOPUS:34447520312
SN - 0953-8178
VL - 19
SP - 657
EP - 673
JO - International Immunology
JF - International Immunology
IS - 5
ER -