title: Codominance of TLR2-dependent and TLR2-independent modulation of MHC class II in Mycobacterium tuberculosis infection in vivo.
abstract: Mycobacterium tuberculosis is an exceptionally successful human pathogen. A major component of this success is the ability of the bacteria to infect immunocompetent individuals and to evade eradication by an adaptive immune response that includes production of the macrophage-activating cytokine, IFN-gamma. Although IFN-gamma is essential for arrest of progressive tuberculosis, it is insufficient for efficacious macrophage killing of the bacteria, which may be due to the ability of M. tuberculosis to inhibit selected macrophage responses to IFN-gamma. In vitro studies have determined that mycobacterial lipoproteins and other components of the M. tuberculosis cell envelope, acting as agonists for TLR2, inhibit IFN-gamma induction of MHC class II. In addition, M. tuberculosis peptidoglycan and IL-6 secreted by infected macrophages inhibit IFN-gamma induction of MHC class II in a TLR2-independent manner. To determine whether TLR2-dependent inhibition of macrophage responses to IFN-gamma is quantitatively dominant over the TLR2-independent mechanisms in vivo, we prepared mixed bone marrow chimeric mice in which the hemopoietic compartment was reconstituted with a mixture of TLR(+/+) and TLR2(-/-) cells. When the chimeric mice were infected with M. tuberculosis, the expression of MHC class II on TLR2(+/+) and TLR2(-/-) macrophages from the lungs of individual infected chimeric mice was indistinguishable. These results indicate that TLR2-dependent and -independent mechanisms of inhibition of responses to IFN-gamma are equivalent in vivo, and that M. tuberculosis uses multiple pathways to abrogate the action of an important effector of adaptive immunity. This work was supported by National Institutes of Health Grants AI 065357-AI 020010.
authors: Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors: Eleanor Z
authors: EZ
authors: Kincaid
authors: Andrea J
authors: AJ
authors: Wolf
authors: Ludovic
authors: L
authors: Desvignes
authors: Sebabrata
authors: S
authors: Mahapatra
authors: Dean C
authors: DC
authors: Crick
authors: Patrick J
authors: PJ
authors: Brennan
authors: Martin S
authors: MS
authors: Pavelka
authors: Joel D
authors: JD
authors: Ernst
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D002678:Chimera / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008074:Lipoproteins / Q000276:immunology; D008168:Lung / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D009169:Mycobacterium tuberculosis; D010457:Peptidoglycan / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology*; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology*
chemical_list: D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D008074:Lipoproteins; D010457:Peptidoglycan; D051195:Toll-Like Receptor 2; D007371:Interferon-gamma