Chronic pneumonia despite adaptive immune response to Mycobacterium bovis BCG in MyD88-deficient mice.
To assess the role of Toll-like receptor (TLR) signalling in host response to mycobacterial infection, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) were infected with the vaccine strain Mycobacterium bovis (BCG), and the immune response and bacterial burden were investigated. Macrophages and dendritic cells from MyD88-deficient mice stimulated in vitro with BCG mycobacterial antigens produced very low levels of proinflammatory cytokines, while the expression of costimulatory molecules such as CD40 and CD86 was preserved. Upon systemic infection with BCG (2 x 10(6) CFU i.v.) MyD88-deficient mice developed confluent chronic pneumonia with two log higher CFU than wild-type mice. Interestingly, the infection was controlled in liver and spleen and there was efficient systemic T-cell priming with high IFNgamma production by CD4+ splenic T cells in MyD88-deficient mice. Lung infiltrating cells showed IFNgamma production by pulmonary CD4+ T cells upon specific restimulation, and a reduced capacity to produce nitric oxide and IL-10. In summary, despite the dramatic reduction of the innate immune response, MyD88-deficient mice were able to mount an efficient T-cell response to mycobacterial antigens, which was however insufficient to control infection in the lung, resulting in chronic pneumonia in MyD88-deficient mice.
Nicolle
Delphine M
DM
Molecular Immunology and Embryology (IEM), CNRS, Orléans, France.
Pichon
Xavier
X
Bouchot
André
A
Maillet
Isabelle
I
Erard
François
F
Akira
Shizuo
S
Ryffel
Bernhard
B
Quesniaux
Valérie F J
VF
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D007110:Immunity, Active; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000502:physiology*; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology
D048868:Adaptor Proteins, Signal Transducing; D000942:Antigens, Bacterial; D000943:Antigens, Differentiation; D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic