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Published online before print June 3, 2003
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© 2003 by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0103026

Received for publication January 17, 2003.
Revised March 31, 2003.
Accepted for publication April 11, 2003.

Article

TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG

Kurt A. Heldwein *, Michael D. Liang *, Tonje K. Andresen *, Karen E. Thomas {dagger}, Aileen M. Marty {ddagger}, Natalia Cuesta {dagger}, Stefanie N. Vogel {dagger}, and Matthew J. Fenton *@

*The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Massachusetts; {dagger}Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore; and {ddagger}Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland

@ To whom correspondence should be addressed. E-mail: mfenton{at}medicine.umaryland.edu.


  Abstract

Toll-like receptor (TLR) proteins mediate cellular activation by microbes and microbial products. To delineate the role of TLR proteins in the development of host immune responses against mycobacteria, wild-type and TLR-deficient mice were infected with nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin (BCG). Two weeks after intraperitoneal challenge with BCG, few bacilli were present in the lungs of wild-type and TLR4-/- mice, whereas bacterial loads were tenfold higher in the lungs of infected TLR2-/- mice. BCG challenge in vitro strongly induced proinflammatory cytokine secretion by macrophages from wild-type and TLR4-/- mice but not by TLR2-/- macrophages. In contrast, intracellular uptake, intracellular bacterial growth, and suppression of intracellular bacterial growth in vitro by interferon-{gamma} (IFN-{gamma}) were similar in macrophages from all three mouse strains, suggesting that BCG growth in the lungs of TLR2-/- mice was a consequence of defective adaptive immunity. Antigenic stimulation of splenocytes from infected wild-type and TLR4-/- mice induced T cell proliferation in vitro, whereas T cells from TLR2-/- mice failed to proliferate. Unexpectedly, activated CD4+ T cells from both TLR-deficient mouse strains secreted little IFN-{gamma} in vitro compared with control T cells. A role for TLR4 in the control of bacterial growth and IFN-{gamma} production in vivo was observed only when mice were infected with higher numbers of BCG. Thus, TLR2 and TLR4 appear to regulate distinct aspects of the host immune response against BCG.

Key Words: cytokines • monocytes/macrophages • bacterial (infections) • inflammation • T lymphocytes






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