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Infection and Immunity, May 2005, p. 2991-2998, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2991-2998.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Efficient Ex Vivo Stimulation of Mycobacterium tuberculosis-Specific T Cells by Genetically Detoxified Bordetella pertussis Adenylate Cyclase Antigen Toxoids

Katalin A. Wilkinson,1 Marcela Simsova,2 Elisabeth Schölvinck,1 Peter Sebo,2 Claude Leclerc,3 H. Martin Vordermeier,4 Stuart J. Dickson,5 Jillian R. Brown,1 Robert N. Davidson,5 Geoffrey Pasvol,1,5 Michael Levin,1 and Robert J. Wilkinson1,5*

Wellcome Trust Center for Research in Clinical Tropical Medicine, Division of Medicine, Imperial College London, Wright Fleming Institute, Norfolk Place, London W2 1PG, United Kingdom,1 Cell and Molecular Biology Division, Institute of Microbiology of the Czech Academy of Sciences, Videnska 1083, CZ-142, Praha 4, Czech Republic,2 Unite de Biologie des Regulations Immunitaires, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France,3 Department of Bacteriology, Veterinary Laboratories Agency, Weybridge, Surrey KT15, United Kingdom,4 Department of Infection and Tropical Medicine, Northwick Park Hospital, Harrow HA1 3UJ, United Kingdom5

Received 9 November 2004/ Returned for modification 15 December 2004/ Accepted 20 December 2004

Mycobacterium tuberculosis is a significant threat to global health. Mycobacterium bovis BCG vaccine provides only partial protection, and the skin test reagent used to aid diagnosis of both active and latent tuberculosis, purified protein derivative (PPD), lacks specificity and sensitivity. The use of genetically detoxified Bordetella pertussis adenylate cyclase toxin (CyaA) as a delivery system for two immunodominant proteins of M. tuberculosis that are of greater specificity than PPD, early-secreted antigenic target 6-kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10), was therefore investigated. CyaA toxoids incorporating these antigens were able to restimulate T cells from more than 91% tuberculosis patients and healthy sensitized donors. Delivery of antigen by CyaA decreased by 10-fold the amount of ESAT-6 and CFP-10 required to restimulate T cells, and in low responders, the overall frequency of gamma interferon-producing cells detected by enzyme-linked immunospot assay was increased (P < 0.01 for both antigens). Delivery of ESAT-6 and CFP-10 by CyaA enabled the detection of both CD4+ and CD8+ T cells: these responses could be blocked by inhibition of major histocompatibility complex class II or class I, respectively. Covalent linkage of antigen to the CyaA vector was required for enhancement to occur, as a mixture of mock CyaA toxoid plus recombinant ESAT-6 did not lead to enhancement. In a simplified whole-blood model to detect tuberculosis infection, the frequency of positive responses to CFP-10 was increased by CyaA delivery, a potentially important attribute that could facilitate the identification of latent infection.

* Corresponding author. Mailing address: Wellcome Trust Center for Research in Clinical Tropical Medicine, Imperial College London, Wright Fleming Institute, Norfolk Place, London W2 1PG, United Kingdom. Phone: (44) 20 7594 3891. Fax: (44) 20 7594 3894. E-mail: r.j.wilkinson{at}imperial.ac.uk.

Editor: J. T. Barbieri

Infection and Immunity, May 2005, p. 2991-2998, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.2991-2998.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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