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.
Highlights
Signaling through immunoreceptor tyrosine-based activation motifs (ITAM) is an important mechanism to control the activation of dendritic cells (DCs)
To determine the requirement for dendritic cell ITAM-containing adaptors (DC-ITAM) signaling in CD8 T cell priming in vivo, we initially performed a series of immunization experiments
Given that DNAX activation protein-12 (Dap12) and FcRc are not required for T cell development and/or function [1], we focused our attention on dendritic cell subsets required for priming and differentiation of CD8 T cells
Summary
Signaling through immunoreceptor tyrosine-based activation motifs (ITAM) is an important mechanism to control the activation of dendritic cells (DCs). DCs express two ITAM containing adaptors: DNAX activation protein-12 (Dap12) and FcRc that channel signals from several immunoreceptors and nonimmunoreceptors (including integrins) and use a canonical ITAM signaling module involving Syk kinase, the Vav GEFs, and SLP76 for downstream signal transduction [1,2,3]. A disruption of DC-ITAM led to enhanced proinflammatory cytokine production after TLR stimulation and an augmented type I interferon response [4,5]. DC-ITAM modulation of TLR, GM-CSF or IFNAR signaling pathways might selectively alter external signals regulating inflammatory effector responses [9]. A deficiency in ITAM signaling alters GM-CSF-driven induction of IRF8, leading to increased Mo-DC differentiation, followed by upregulation of IL-12 production. Our data provide evidence for cross-talk between ITAM and TLR or GM-CSF signaling pathways, which modulates Mo-DC differentiation and IL-12 cytokine-driven regulation of CD8 T cell responses
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