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Infection and Immunity, April 2003, p. 1763-1773, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.1763-1773.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Differential Effects of Control and Antigen-Specific T Cells on Intracellular Mycobacterial Growth

S. Worku and D. F. Hoft*

Saint Louis University Center for Vaccine Development, Department of Internal Medicine, St. Louis, Missouri 63110

Received 21 August 2002/ Returned for modification 14 October 2002/ Accepted 9 January 2003

We investigated the effects of peripheral blood mononuclear cells expanded with irrelevant control and mycobacterial antigens on the intracellular growth of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in human macrophages. More than 90% of the cells present after 1 week of in vitro expansion were CD3+. T cells were expanded from purified protein derivative-negative controls, persons with latent tuberculosis, and BCG-vaccinated individuals. T cells expanded with nonmycobacterial antigens enhanced the intracellular growth of BCG in suboptimal cultures of macrophages. T cells expanded with live BCG or lysates of Mycobacterium tuberculosis directly inhibited intracellular BCG. Recent intradermal BCG vaccination significantly enhanced the inhibitory activity of T cells expanded with mycobacterial antigens (P < 0.02), consistent with the induction of memory-immune inhibitory T-cell responses. Selected mycobacterial antigens (Mtb41 > lipoarabinomannan > 38kd > Ag85B > Mtb39) expanded inhibitory T cells, demonstrating the involvement of antigen-specific T cells in intracellular BCG inhibition. We studied the T-cell subsets and molecular mechanisms involved in the memory-immune inhibition of intracellular BCG. Mycobacteria-specific {gamma}{delta} T cells were the most potent inhibitors of intracellular BCG growth. Direct contact between T cells and macrophages was necessary for the BCG growth-enhancing and inhibitory activities mediated by control and mycobacteria-specific T cells, respectively. Increases in tumor necrosis factor alpha, interleukin-6, transforming growth factor ß, and vascular endothelial growth factor mRNA expression were associated with the enhancement of intracellular BCG growth. Increases in gamma interferon, FAS, FAS ligand, perforin, granzyme, and granulysin mRNA expression were associated with intracellular BCG inhibition. These culture systems provide in vitro models for studying the opposing T-cell mechanisms involved in mycobacterial survival and protective host immunity.

* Corresponding author. Mailing address: Division of Infectious Diseases and Immunology, St. Louis University Health Sciences Center, St. Louis, MO 63110. Phone: (314) 577-8649. Fax: (314) 771-3816. E-mail: hoftdf{at}slu.edu.

Editor: S. H. E. Kaufmann

Infection and Immunity, April 2003, p. 1763-1773, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.1763-1773.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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