期刊
INTERNATIONAL IMMUNOLOGY
卷 19, 期 5, 页码 657-673出版社
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxm031
关键词
2-C-methyl-D-erythritol-4 phosphate pathway; microbial immunity; prenyl pyrophosphate antigens; gamma delta T cells
类别
资金
- NCRR NIH HHS [S10 RR019352] Funding Source: Medline
- NIAID NIH HHS [U54 AI057160] Funding Source: Medline
- NIAMS NIH HHS [R01 AR45504, R01 AR045504] Funding Source: Medline
Human V gamma 2V delta 2 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-enyI pyrophosphate (HMBPP) has been identified as a metabolite in the 2-C-methyl-D-erythritol-4 phosphate (MEP) pathway for isoprenold biosynthesis that is used by many bacteria and protozoan parasites. We find that HMBPP is the major V gamma 2V delta 2 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 V-gamma 2V delta 2 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 V gamma 2V delta 2 TCR elements and is present at birth. Importantly, we show that bacterial HMBPP levels correlated with their ability to expand V gamma 2V delta 2 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 V gamma 2V delta 2 T cells in vivo. This preferential stimulation by a common microbial isoprenoid metabolite allows V-gamma 2V delta 2 T cells to respond to a broad array of pathogens using this pathway.
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