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Infect Immun, July 1998, p. 3190-3197, Vol. 66, No. 7
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Identification of New Cytotoxic T-Cell Epitopes on the 38-Kilodalton Lipoglycoprotein of Mycobacterium tuberculosis by Using Lipopeptides

Dora P. A. J. da Fonseca,1,* Dianne Joosten,1 Ruurd van der Zee,2 Danny L. Jue,3 Mahavir Singh,4 Hans M. Vordermeier,5 Harm Snippe,1 and André F. M. Verheul1

Eijkman-Winkler Institute for Microbiology, Infectious Diseases, and Inflammation, Section Vaccines, Academic Hospital Utrecht, Utrecht University, 3584 CX Utrecht,1 and Institute of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, 3508 TD Utrecht,2 The Netherlands; Biotechnology Core Facility, National Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 303333; GBF---German National Research Center for Biotechnology, 38124 Braunschweig, Germany4; and Veterinary Laboratories Agency, Bacteriology, TB Research Group, New Haw, Addlestone, Surrey KT13 3NB, United Kingdom5

Received 9 March 1998/Accepted 22 April 1998

Induction of cytotoxic T lymphocytes (CTLs) by vaccination has been shown to protect against bacterial, viral, and tumoral challenge. The aim of this study was to identify CTL epitopes on the 38-kDa lipoglycoprotein from Mycobacterium tuberculosis. The identification of these CTL epitopes was based on synthesizing peptides designed from the 38-kDa lipoglycoprotein, with known major histocompatibility complex class I (MHC-I) binding motifs (H-2Db), and studying their ability to up-regulate and stabilize MHC-I molecules on the mouse lymphoma cell line RMA-S. To improve the capacity of the identified peptides to induce CTL responses in mice, palmitic acid with a cysteine-serine-serine spacer amino acid sequence was attached to the amino terminus of the peptide. Two of five peptides with H-2Db binding motifs and their corresponding lipopeptides up-regulated and stabilized the H-2Db molecules on RMA-S cells. Both lipopeptides, in combination with incomplete Freund's adjuvant, induced CTL responses in C57BL/6 (H-2b) mice. Moreover, the lipopeptide induced stronger CTL responses than the peptide. The capacity of the various lipopeptides to induce CTL displayed a good relationship with the ability of the (lipo)peptide to up-regulate and to stabilize H-2Db molecules. The capacity of the peptides and lipopeptides to up-regulate and stabilize MHC-I expression can therefore be used to predict their potential to function as a CTL epitope. The newly identified CTL epitopes and their lipid derivatives provide us with important information for future M. tuberculosis vaccine design.

* Corresponding author. Mailing address: Eijkman-Winkler Institute for Microbiology, Infectious Diseases, and Inflammation, Section Vaccines, AZU, Rm. G04.614, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Phone: 31-30-2506525. Fax: 31-30-2541770. E-mail: D.Fonseca{at}lab.azu.nl.

Infect Immun, July 1998, p. 3190-3197, Vol. 66, No. 7
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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Copyright © 1998 by the American Society for Microbiology. All rights reserved.