MyD88-dependent activation of B220-CD11b+LY-6C+ dendritic cells during Brucella melitensis infection.
IFN-gamma is a key cytokine controlling Brucella infection. One of its major function is the stimulation of Brucella-killing effector mechanisms, such as inducible NO synthase (iNOS)/NOS2 activity, in phagocytic cells. In this study, an attempt to identify the main cellular components of the immune response induced by Brucella melitensis in vivo is made. IFN-gamma and iNOS protein were analyzed intracellularly using flow cytometry in chronically infected mice. Although TCRbeta(+)CD4(+) cells were the predominant source of IFN-gamma in the spleen, we also identified CD11b(+)LY-6C(+)LY-6G(-)MHC-II(+) cells as the main iNOS-producing cells in the spleen and the peritoneal cavity. These cells appear similar to inflammatory dendritic cells recently described in the mouse model of Listeria monocytogenes infection and human psoriasis: the TNF/iNOS-producing dendritic cells. Using genetically deficient mice, we demonstrated that the induction of iNOS and IFN-gamma-producing cells due to Brucella infection required TLR4 and TLR9 stimulation coupled to Myd88-dependent signaling pathways. The unique role of MyD88 was confirmed by the lack of impact of Toll-IL-1R domain-containing adaptor inducing IFN-beta deficiency. The reduction of IFN-gamma(+) and iNOS(+) cell frequency observed in MyD88-, TLR4-, and TLR9-deficient mice correlated with a proportional lack of Brucella growth control. Taken together, our results provide new insight into how immune responses fight Brucella infection.
Copin
Richard
R
Unité de Recherche en Biologie Moléculaire, Laboratoire d'Immunologie et de Microbiologie, Faculté Universitaire Notre Dame de la Paix, Namur, Belgium.
De Baetselier
Patrick
P
Carlier
Yves
Y
Letesson
Jean-Jacques
JJ
Muraille
Eric
E
D000818:Animals; D000950:Antigens, Ly / Q000502:physiology*; D017347:Brucella melitensis; D002006:Brucellosis / Q000276:immunology*; D039481:CD11b Antigen / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D007371:Interferon-gamma / Q000502:physiology; D017493:Leukocyte Common Antigens / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000502:physiology
D000950:Antigens, Ly; D039481:CD11b Antigen; C494192:Ly-6C antigen, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D017493:Leukocyte Common Antigens