title: On/off TLR signaling decides proinflammatory or tolerogenic dendritic cell maturation upon CD1d-mediated interaction with invariant NKT cells.
abstract: Invariant NKT (iNKT) cells play an effector/adjuvant function during antimicrobial and antitumoral immunity and a regulatory role to induce immune tolerance and prevent autoimmunity. iNKT cells that differentially modulate adaptive immunity do not bear a unique phenotype and/or specific cytokine secretion profile, thus opening questions on how a single T cell subset can exert opposite immunological tasks. In this study, we show that iNKT cells perform their dual roles through a single mechanism of action relying on the cognate interaction with myeloid dendritic cells (DCs) and leading to opposite effects depending on the presence of other maturation stimuli simultaneously acting on DCs. The contact of murine purified iNKT cells with immature autologous DCs directly triggers the tolerogenic maturation of DCs, rendering them able to induce regulatory T cell differentiation and prevent autoimmune diabetes in vivo. Conversely, the interaction of the same purified iNKT cells with DCs, in the presence of simultaneous TLR4 stimulation, significantly enhances proinflammatory DC maturation and IL-12 secretion. The different iNKT cell effects are mediated through distinct mechanisms and activation of different molecular pathways within the DC: CD1d signaling and activation of the ERK1/2 pathway for the tolerogenic action, and CD40-CD40L interaction and NF-κB activation for the adjuvant effect. Our data suggest that the DC decision to undergo proinflammatory or tolerogenic maturation results from the integration of different signals received at the time of iNKT cell contact and could have important therapeutic implications for exploiting iNKT cell adjuvant/regulatory properties in autoimmune diseases, infections, and cancer.
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Caielli
authors.forename: Cristina
authors.initials: C
authors.lastname: Conforti-Andreoni
authors.forename: Caterina
authors.initials: C
authors.lastname: Di Pietro
authors.forename: Vera
authors.initials: V
authors.lastname: Usuelli
authors.forename: Ester
authors.initials: E
authors.lastname: Badami
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Malosio
authors.forename: Marika
authors.initials: M
authors.lastname: Falcone
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D007108:Immune Tolerance; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D055611:Natural Killer T-Cells / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: D055610:Antigens, CD1d; D019013:CD40 Antigens; C526879:Cd1d1 protein, mouse; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D023201:CD40 Ligand; D018664:Interleukin-12; D048052:Mitogen-Activated Protein Kinase 3