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Induction of CD8 T Cells against a Novel Epitope in TB10.4: Correlation with Mycobacterial Virulence and the Presence of a Functional Region of Difference-1¹

Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark

Although infection with Mycobacterium tuberculosis (M.tb) induces a robust CD8 T cell response, the role of CD8 T cells in the defense against M.tb, and the mechanisms behind the induction of CD8 T cells, is still not clear. TB10.4 is a recently described Ag that is expressed by both bacillus Calmette-Guérin (BCG) and M.tb. In the present study, we describe a novel CD8 T cell epitope in TB10.4, TB10.4^3-11. We show that TB10.4^3-11-specific CD8 T cells are induced at the onset of infection and are present throughout the infection in high numbers. TB10.4^3-11 CD8 T cells were recruited to the site of infection and expressed CD44, TNF-, and IFN-. In addition, TB10.4^3-11 CD8 T cells showed an up-regulation of FasL and LAMP-1/2 (CD107A/B), which correlated with a strong in vivo cytolytic activity. The induction of TB10.4^3-11-specific CD8 T cells was less pronounced following infection with BCG compared to infection with M.tb. By using a rBCG expressing the genetic region of difference-1 (RD1), we show that the presence of a functional RD1 region increases the induction of TB10.4^3-11-specific CD8 T cells as well as the bacterial virulence. Finally, as an M.tb variant lacking the genetic region RD1 also induced a significant amount of TB10.4^3-11-specific CD8 T cells, and exhibited increased virulence compared with BCG, our data suggest that virulence in itself is also involved in generating a robust CD8 T cell response against mycobacterial epitopes, such as TB10.4^3-11.

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 partially supported by Danish Research Agency, Ministry of Science, Technology and Innovation.

² Address correspondence and reprint requests to Dr. Jes Dietrich, Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark. E-mail address: JDI{at}ssi.dk

³ Abbreviations used in this paper: M.tb, Mycobacterium tuberculosis; TB, tuberculosis; BCG, bacillus Calmette-Guérin; MHC-I, MHC class I; MHC-II, MHC class II; RD1, region of difference-1.