Increased TLR responses in dendritic cells lacking the ITAM-containing adapters DAP12 and FcRγ

Abstract

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 FcεRIγ-chain (FcRγ) are required for negative regulation of TLR responses in bone marrow-derived dendritic cells (DC). Loss of both DAP12 and FcRγ enhanced the proinflammatory 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 FcRγ had a greater enhancement of maturation and cytokine production, though to a lesser extent than DC lacking both DAP12 and FcRγ. Additionally, antigen-specific T cell proliferation was enhanced by DAP12-/-FcRγ-/- DC relative to wild-type DC after maturation. Similar to DAP12-/-FcRγ-/- 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 FcRγ for negative regulation of TLR signaling. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.