CD40-TRAF6 and autophagy-dependent anti-microbial activity in macrophages.
A fundamental question in host-pathogen interaction is to determine if the immune system activates fusion with the lysosomes to eradicate pathogens. We recently reported that this task is accomplished by the interaction between CD40 expressed on macrophages and CD154 expressed on activated CD4+ T cells. CD40 stimulation of macrophages induces vacuole-lysosome fusion through autophagy and results in killing of the obligate intracellular pathogen Toxoplasma gondii. This response is independent of IFN-gamma, STAT1 and p47 GTPases. We now report that vacuole-lysosome fusion is dependent on synergy between TRAF6 signaling downstream of CD40 and TNF-alpha. These studies identified a new paradigm by which T cells eradicate an intracellular pathogen within macrophages.
Subauste
Carlos S
CS
Department of Ophthalmology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA. carlos.subauste@case.edu
Andrade
Rosa M
RM
Wessendarp
Matthew
M
D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014122:Toxoplasma / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism
D019013:CD40 Antigens; D011993:Recombinant Fusion Proteins; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand