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Conserved Mycobacterial Lipoglycoproteins Activate TLR2 but Also Require Glycosylation for MHC Class II-Restricted T Cell Activation¹

Peter A. Sieling^2,*, Preston J. Hill^2,, Karen M. Dobos^2,, Kerry Brookman, Andrew M. Kuhlman, Mario Fabri^*, Stephan R. Krutzik^*, Thomas H. Rea^¶, Darragh G. Heaslip, John T. Belisle^3, and Robert L. Modlin^3,4,*,,

^* Division of Dermatology, Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095; Department of Microbiology, Immunology, and Pathology, College of Veterinarian Medicine and Biomedical Sciences, Colorado State University, Ft. Collins, CO 80523; and ^¶ Section of Dermatology, Keck School of Medicine at University of Southern California, Los Angeles, CA 90033

CD4⁺ T cell clones derived from a leprosy lesion and patient blood were used to monitor the isolation and identification of an Ag associated with the self-limited form of the disease. Biochemical purification and genetic analysis identified the T cell Ag as a conserved mycobacterial lipoglycoprotein LprG. LprG-mediated activation of CD4⁺ T cells required specific MHC class II restriction molecules and intracellular processing. Although LprG activated TLR2, this alone was not sufficient to stimulate or inhibit T cell activation. A striking finding was that the carbohydrate moieties of LprG were required for optimal T cell activation, because recombinant LprG produced in Escherichia coli, or recombinant LprG produced in Mycobacterium smegmatis and digested by -mannosidase, did not activate T cells. This study demonstrates that the universe of bacterial T cell Ags includes lipoglycoproteins, which act as TLR2 ligands but also require glycosylation for MHC class II-restricted T cell activation in vivo.

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 in part by grants from the National Institutes of Health (AI22553 and AI47868 to R.L.M.) the Deutsche Forschungsgemeinschaft (FA849/1-1 to M.F.), and material support through National Institutes of Health Contract NO1 AI75320 (to J.T.B.).

² P.A.S., P.J.H., and K.M.D. contributed equally to this work.

³ J.T.B. and R.L.M. contributed equally to this work and share senior authorship.

⁴ Address correspondence and reprint requests to Dr. Robert L. Modlin, Division of Dermatology, David Geffen School of Medicine, University of California, 52-121 Center for Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail address: rmodlin{at}mednet.ucla.edu

⁵ Abbreviations used in this paper: CV, column volume; HIC, hydrophobic interaction chromatography; SE, size eclusion.