Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program.
Immature monocyte-derived dendritic cells (DC) strongly express the endocytic mannose receptor (MR). Addition of a specific anti-MR mAb (clone PAM-1) for 24 h to cultures of immature DC induced phenotypical and functional maturation of the cells, assessed as up-regulation of costimulatory molecules and CD83, and chemotactic response to CCL19. A different isotype-matched anti-MR mAb (clone 19.2) had no significant effect. Engagement of MR with mAb PAM-1 induced the production of the anti-inflammatory cytokines IL-10, IL-1R antagonist, and of the nonsignaling IL-1R type II. In contrast IL-1beta, TNF, and IL-12 were not produced. PAM-1-treated DC were unable to polarize Th1 effector cells and did not secrete the chemokines CXCL10 and CCL19; in turn, they produced large amounts of CCL22 and CCL17, thus favoring the amplification of Th2 circuits. T cells cocultured with PAM-1-matured DC initially proliferated but later became anergic and behaved as suppressor/regulatory cells. Natural ligands binding to MR had differential effects. MUC III (a partially purified mucin), biglycan (a purified complex proteoglycan), and mannosylated lipoarabinomannan from Mycobacterium tuberculosis affected cytokine production with high IL-10, IL-1R antagonist, IL-1R type II, and inhibition of IL-12. In contrast, mannan, dextran, and thyroglobulin had no significant effect. In conclusion, the appropriate engagement of the MR by mAb PAM-1 and selected natural ligands elicit a secretory program in mono-derived DC characterized by a distinct profile of cytokines/chemokines with the ability to dampen inflammation and to inhibit the generation of Th1-polarized immune responses.
Department of Immunology, Istituto Mario Negri, Milan, Italy.
Marcello
M
Chieppa
Giancarlo
G
Bianchi
Andrea
A
Doni
Annalisa
A
Del Prete
Marina
M
Sironi
Gordana
G
Laskarin
Paolo
P
Monti
Lorenzo
L
Piemonti
Andrea
A
Biondi
Alberto
A
Mantovani
Martino
M
Introna
Paola
P
Allavena
D000911:Antibodies, Monoclonal / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism / Q000502:physiology; D017635:Clonal Anergy / Q000276:immunology; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D008024:Ligands; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D008024:Ligands; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D016753:Interleukin-10; D018664:Interleukin-12