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T Cells1
* Department of Internal Medicine, Division of Rheumatology and
Interdisciplinary Graduate Program in Immunology, University of Iowa College of Medicine, Iowa City, IA 52242;
Department of Medicinal Chemistry, University of Utah School of Pharmacy, Salt Lake City, UT 84112;
Department of Chemistry and Center for Biophysics and Computational Biology, Urbana, IL 61801; and
¶ Department of Chemistry, University of Minnesota, Minneapolis, MN 55455
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2 T cells comprise the major subset of peripheral blood T cells in humans and expand during infections by recognizing small nonpeptide prenyl pyrophosphates. These molecules include (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP), a microbial isoprenoid intermediate, and isopentenyl pyrophosphate, an endogenous isoprenoid intermediate. Recognition of these nonpeptide Ags is mediated by the V2V2 T cell Ag receptor. Several findings suggest that prenyl pyrophosphates are presented by an Ag-presenting molecule: contact between T cells and APC is required, the Ags do not bind the V2V2 TCR directly, and Ag recognition is abrogated by TCR mutations in CDRs distant from the putative Ag recognition site. Identification of the putative Ag-presenting molecule, however, has been hindered by the inability to achieve stable association of nonpeptide prenyl pyrophosphate Ags with the presenting molecule. In this study, we show that photoaffinity analogues of HMBPP, meta/para-benzophenone-(methylene)-prenyl pyrophosphates (m/p-BZ-(C)-C5-OPP), can crosslink to the surface of tumor cell lines and be presented as Ags to T cells. Mutant tumor cell lines lacking MHC class I, MHC class II, β2-microglobulin, and CD1, as well as tumor cell lines from a variety of tissues and individuals, will all crosslink to and present m-BZ-C5-OPP. Finally, pulsing of BZ-(C)-C5-OPP is inhibited by isopentenyl pyrophosphate and an inactive analog, suggesting that they bind to the same molecule. Taken together, these results suggest that nonpeptide Ags are presented by a novel-Ag-presenting molecule that is widely distributed and nonpolymorphic, but not classical MHC class I, MHC class II, or CD1.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Disease (AR45504), the National Institute of Allergy and Infectious Diseases (Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, AI057160), and the National Cancer Institute (CA113874) to C.T.M., the National Institute of Neurological Disorders and Stroke (NS29632) to G.D.P., and the National Institutes of General Medical Sciences (GM073216 and GM58442) to E.O. and M.D., respectively.
2 Current address: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive Singapore 169610, Singapore.
3 Current address: Supergen, Inc., 2401 South Foothill Drive, Salt Lake City, UT 84109.
4 Address correspondence and reprint requests to Dr. Craig T. Morita, Department of Internal Medicine, Division of Rheumatology and the Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, EMRB 400F, Iowa City, IA 52242. E-mail address: Craig-Morita{at}uiowa.edu
5 Abbreviations used in this paper: HMBPP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; β2M, β2-microglobulin; BZ, benzophenone; BrHPCP, bromohydrin pyrophosphonate; BrHPP, bromohydrin pyrophosphate; DATFP, diazo-3,3,3-trifluoropropionyloxy; EPP, ethyl pyrophosphate; FPP, farnesyl pyrophosphate; FPPS, FPP synthase; GPP, geranyl pyrophosphate; IPP, isopentenyl pyrophosphate; m, meta; OPP, pyrophosphate; p, para.
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