Increased TLR responses in dendritic cells lacking the ITAM-containing adapters DAP12 and FcRgamma.
The inhibitory effect of DAP12 on macrophages has been revealed by examining myeloid cells from DAP12-deficient mice. In this report, we demonstrate that both DAP12 and the FcepsilonRIgamma-chain (FcRgamma) are required for negative regulation of TLR responses in bone marrow-derived dendritic cells (DC). Loss of both DAP12 and FcRgamma enhanced the pro-inflammatory cytokine production and maturation of DC after TLR stimulation, resulting in a greater percentage of DC that produced IL-12 p40, TNF, and IL-6, and expressed high levels of MHC class II, CD80, and CD86. Whereas DC lacking only DAP12 showed some increased TLR responses, those lacking only FcRgamma had a greater enhancement of maturation and cytokine production, though to a lesser extent than DC lacking both DAP12 and FcRgamma. Additionally, antigen-specific T cell proliferation was enhanced by DAP12(-/-)FcRgamma(-/-) DC relative to wild-type DC after maturation. Similar to DAP12(-/-)FcRgamma(-/-) DC, Syk-deficient DC also had increased inflammatory cytokine production, maturation, and antigen presentation. These results confirm the inhibitory effect of immunoreceptor tyrosine-based activation motif (ITAM) signaling in myeloid cells and show that DC and macrophages differ in their dependence on the ITAM-containing adapters DAP12 and FcRgamma for negative regulation of TLR signaling.
Chu
Ching-Liang
CL
Immunology Research Center, National Health Research Institutes, Taiwan.
Yu
Yen-Ling
YL
Shen
Kuan-Yin
KY
Lowell
Clifford A
CA
Lanier
Lewis L
LL
Hamerman
Jessica A
JA
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000172:deficiency*; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C485701:Fcgr1 protein, mouse; D017452:Receptors, IgG; D051193:Toll-Like Receptors; C484963:Tyrobp protein, mouse