CD2-associated protein regulates plasmacytoid dendritic cell migration, but is dispensable for their development and cytokine production.
Plasmacytoid dendritic cells (pDCs) are a dendritic cell subset that secrete type I IFNs in response to microbial stimuli. The scaffold protein, CD2-associated protein (CD2AP), is a marker of human pDCs as it is highly expressed in this cell type. Recently, in human pDCs, decreased CD2AP expression appeared to enhance the production of type I IFNs via an inhibitory receptor-induced signaling cascade. In this study, we sought to determine the role of CD2AP in murine pDCs using CD2AP knockout (KO) mice. CD2AP was dispensable for the development of pDCs and for the upregulation of activation markers following stimulation. Loss of CD2AP expression did not affect the production of type I IFNs stimulated by TLR ligation, and only slightly impaired type I IFN production when inhibitory pathways were engaged in vitro. This was also confirmed by showing that CD2AP deficiency did not influence type I IFN production by pDCs in vivo. Because CD2AP plays a role in regulating actin dynamics, we examined the actin cytoskeleton in pDCs and found that activated CD2AP KO pDCs had significantly higher levels of actin polymerization than wild-type pDCs. Using two different inflammation models, we found that CD2AP KO pDCs have a defect in lymph node migration, correlating with the defects in actin dynamics. Our work excludes a role for CD2AP in the regulation of type I IFNs in pDCs, and suggests that the major function of CD2AP is on the actin cytoskeleton, affecting migration to local lymph nodes under conditions of inflammation.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Subhashini
S
Srivatsan
Melissa
M
Swiecki
Karel
K
Otero
Marina
M
Cella
Andrey S
AS
Shaw
D000199:Actins / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology / Q000648:ultrastructure; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology*; D008221:Lymphoid Tissue / Q000166:cytology; D051379:Mice; D020297:Mice, Congenic; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology; D011828:Radiation Chimera; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D018116:Vesiculovirus / Q000276:immunology
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D016207:Cytokines; D003598:Cytoskeletal Proteins; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha