title: TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG.
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.
authors.affiliation: The Pulmonary Center, Department of Medicine, Boston University School of Medicine, Massachusetts, USA.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Heldwein
authors.forename: Michael D
authors.initials: MD
authors.lastname: Liang
authors.forename: Tonje K
authors.initials: TK
authors.lastname: Andresen
authors.forename: Karen E
authors.initials: KE
authors.lastname: Thomas
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Marty
authors.forename: Natalia
authors.initials: N
authors.lastname: Cuesta
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fenton
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D006720:Homozygote; D007111:Immunity, Cellular; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000382:microbiology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000502:physiology*; D013154:Spleen / Q000378:metabolism; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology
chemical_list: D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D007371:Interferon-gamma