Annexin-1-deficient dendritic cells acquire a mature phenotype during differentiation.
Dendritic cells play a key role in the adaptive immune system by influencing T-cell differentiation. Annexin-1 (Anx-A1) has recently been shown to modulate the adaptive immune response by regulating T-cell activation and differentiation. Here we investigated the role of endogenous Anx-A1 in dendritic cells as major cellular counterpart of T-cell-driven immune response. We found that Anx-A1(-/-) bone marrow-derived dendritic cells show an increased number of CD11c(+) cells expressing high levels of some maturation markers, such as CD40, CD54, and CD80, coupled to a decreased capacity to take up antigen compared to control Anx-A1(+/+) cells. However, analysis of LPS-treated dendritic cells from Anx-A1(-/-) mice demonstrated a diminished up-regulation of maturation markers, a decreased migratory activity in vivo, and an attenuated production of the inflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-12. This defect was also accompanied by impaired nuclear factor (NF)-kappaB/DNA-binding activity and lack of Anx-A1 signaling, as demonstrated by the reduced activation of extracellular-signal regulated kinase (ERK)1/2 and Akt compared to cells from control littermates. As a consequence of this phenotype, Anx-A1(-/-) dendritic cells showed an impaired capacity to stimulate T-cell proliferation and differentiation in mixed leukocyte reaction. Together, these findings suggest that inhibition of Anx-A1 expression or function in dendritic cells might represent a useful way to modulate the adaptive immune response and pathogen-induced T-cell-driven immune diseases.
Huggins
Anthony
A
William Harvey Research Institute, Barts and The London School of Medicine, London, UK.
Paschalidis
Nikolaos
N
Flower
Roderick J
RJ
Perretti
Mauro
M
D'Acquisto
Fulvio
F
D000818:Animals; D017305:Annexin A1 / Q000032:analysis* / Q000378:metabolism; D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000502:physiology; D003911:Dextrans / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D017305:Annexin A1; D018122:B7-1 Antigen; D015415:Biomarkers; D039521:CD11c Antigen; D019013:CD40 Antigens; D016207:Cytokines; D003911:Dextrans; D005456:Fluorescent Dyes; D008070:Lipopolysaccharides; D016650:Fluorescein-5-isothiocyanate