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 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 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.