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International Immunology Advance Access published online on April 19, 2007
International Immunology, doi:10.1093/intimm/dxm031
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Preferential recognition of a microbial metabolite by human V{gamma}2V{delta}2 T cells

Kia-Joo Puan1, Chenggang Jin1, Hong Wang1, Ghanashyam Sarikonda1, Amy M. Raker1, Hoi K. Lee1, Megan I. Samuelson1, Elisabeth Märker-Hermann2, Ljiljana Pasa-Tolic3, Edward Nieves4, José-Luis Giner5, Tomohisa Kuzuyama6 and Craig T. Morita1

1 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
2 Division of Rheumatology, Immunology and Nephrology, Department of Internal Medicine IV, Dr. Horst Schmidt Kliniken GmbH, 65191 Wiesbaden, Germany
3 Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA
4 Laboratory for Molecular Analysis and Proteomics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
5 Department of Chemistry, State University of New York-ESF, Syracuse, NY 13210, USA
6 Laboratory of Cell Biotechnology, Biotechnology Research Center, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan

Correspondence to: Correspondence to: C. T. Morita; E-mail: craig-morita{at}uiowa.edu

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-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 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.

Keywords: 2-C-methyl-D-erythritol-4 phosphate pathway, microbial immunity, prenyl pyrophosphate antigens, {gamma}{delta} T cells

Transmitting editor: W. Yokoyama

Received 21 December 2006, accepted 23 February 2007.


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