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Infection and Immunity, October 2002, p. 5446-5453, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5446-5453.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Epitope Mapping of the Immunodominant Antigen TB10.4 and the Two Homologous Proteins TB10.3 and TB12.9, Which Constitute a Subfamily of the esat-6 Gene Family

Rikke Louise Vinther Skjøt,1 Inger Brock,1 Sandra M. Arend,2 Martin E. Munk,1 Michael Theisen,1 Tom H. M. Ottenhoff,2 and Peter Andersen1*

Department of TB Immunology, Statens Serum Institute, Copenhagen, Denmark,1 Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands2

Received 30 January 2002/ Returned for modification 16 April 2002/ Accepted 17 July 2002

The human T-cell recognition of the low-molecular-mass culture filtrate antigen TB10.4 was evaluated in detail. The molecule was strongly recognized by T cells isolated from tuberculosis (TB) patients and from BCG-vaccinated donors. The epitopes on TB10.4 were mapped with overlapping peptides and found to be distributed throughout the molecule. The broadest response was found in TB patients, whereas the response in BCG-vaccinated donors was focused mainly toward a dominant epitope located in the N terminus (amino acids 1 to 18). The gene encoding TB10.4 was found to belong to a subfamily within the esat-6 family that consists of the three highly homologous proteins TB10.4, TB10.3, and TB12.9 (Rv0288, Rv3019c, and Rv3017c, respectively). Southern blot analysis combined with database searches revealed that the three members of the TB10.4 family were present only in strains of the Mycobacterium tuberculosis complex, including BCG, and M. kansasii, whereas other atypical mycobacteria had either one (M. avium, M. intracellulare, and M. marinum) or none (M. scrofulaceum, M. fortuitum, and M. szulgai) of the genes. The fine specificity of the T-cell response to the three closely related esat-6 family members was markedly different, with only a few epitopes shared between the molecules. Minimal differences in the amino acid sequence translated into large differences in recognition by T cells and secretion of gamma interferon. In general, the peptides from TB10.4 stimulated the largest responses, but epitopes unique to both TB10.3 and TB12.9 were found. The relevance of the findings for TB vaccine development and as a potential mechanism for immune evasion is discussed.

* Corresponding author. Mailing address: Department of TB Immunology, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark. Phone: 45-32-68-34-62. Fax: 45-32-68-30-35. E-mail: pa{at}ssi.dk.

Editor: S. H. E. Kaufmann

Infection and Immunity, October 2002, p. 5446-5453, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5446-5453.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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