title: Loss of DAP12 and FcRγ drives exaggerated IL-12 production and CD8(+) T cell response by CCR2(+) Mo-DCs.
abstract: Dap12 and FcRγ, the two transmembrane ITAM-containing signaling adaptors expressed in dendritic cells (DC), are implicated in the regulation of DC function. Several activating and adhesion receptors including integrins require these chains for their function in triggering downstream signaling and effector pathways, however the exact role(s) for Dap12 and FcRγ remains elusive as their loss can lead to both attenuating and enhancing effects. Here, we report that mice congenitally lacking both Dap12 and FcRγ chains (DF) show a massively enhanced effector CD8(+) T cell response to protein antigen immunization or West Nile Virus (WNV) infection. Thus, immunization of DF mice with MHCI-restricted OVA peptide leads to accumulation of IL-12-producing monocyte-derived dendritic cells (Mo-DC) in draining lymph nodes, followed by vastly enhanced generation of antigen-specific IFNγ-producing CD8(+) T cells. Moreover, DF mice show increased viral clearance in the WNV infection model. Depletion of CCR2+ monocytes/macrophages in vivo by administration anti-CCR2 antibodies or clodronate liposomes completely prevents the exaggerated CD8+ T cell response in DF mice. Mechanistically, we show that the loss of Dap12 and FcRγ-mediated signals in Mo-DC leads to a disruption of GM-CSF receptor-induced STAT5 activation resulting in upregulation of expression of IRF8, a transcription factor. Consequently, Dap12- and FcRγ-deficiency exacerbates GM-CSF-driven monocyte differentiation and production of inflammatory Mo-DC. Our data suggest a novel cross-talk between DC-ITAM and GM-CSF signaling pathways, which controls Mo-DC differentiation, IL-12 production, and CD8(+) T cell responses.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Grzegorz B
authors.initials: GB
authors.lastname: Gmyrek
authors.forename: Holly M
authors.initials: HM
authors.lastname: Akilesh
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.forename: Anja
authors.initials: A
authors.lastname: Fuchs
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Miller
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Sandoval
authors.forename: Kathleen C F
authors.initials: KC
authors.lastname: Sheehan
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology*; D054390:Receptors, CCR2 / Q000378:metabolism*; D017452:Receptors, IgG / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism; D014902:West Nile virus / Q000187:drug effects / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000956:Antigens, Viral; C485701:Fcgr1 protein, mouse; D054390:Receptors, CCR2; D017452:Receptors, IgG; D051193:Toll-Like Receptors; C484963:Tyrobp protein, mouse; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor