title: Role of CD40 ligation in dendritic cell semimaturation.
abstract: BACKGROUND
  DC are among the first antigen presenting cells encountering bacteria at mucosal surfaces, and play an important role in maintenance of regular homeostasis in the intestine. Upon stimulation DC undergo activation and maturation and as initiators of T cell responses they have the capacity to stimulate naïve T cells. However, stimulation of naïve murine DC with B. vulgatus or LPS at low concentration drives DC to a semimature (sm) state with low surface expression of activation-markers and a reduced capacity to activate T-cells. Additionally, semimature DC are nonresponsive to subsequent TLR stimulation in terms of maturation, TNF-α but not IL-6 production. Ligation of CD40 is an important mechanism in enhancing DC maturation, function and capacity to activate T-cells. We investigated whether the DC semimaturation can be overcome by CD40 ligation.
  
  
  RESULTS
  Upon CD40 ligation smDC secreted IL-12p40 but not the bioactive heterodimer IL-12p70. Additionally, CD40 ligation of smDC resulted in an increased production of IL-6 but not in an increased expression of CD40. Analysis of the phosphorylation pattern of MAP kinases showed that in smDC the p38 phosphorylation induced by CD40 ligation is inhibited. In contrast, phosphorylation of ERK upon CD40 ligation was independent of the DC maturation state.
  
  
  CONCLUSIONS
  Our data show that the semimature differentiation state of DC can not be overcome by CD40 ligation. We suggest that the inability of CD40 ligation in overcoming DC semimaturation might contribute to the tolerogenic phenotype of semimature DC and at least partially account for maintenance of intestinal immune homeostasis.
authors.affiliation: Institute for Medical Microbiology and Hygiene, University Hospital of Tübingen, 72076 Elfriede-Aulhorn-Str. 6, Tübingen, D-72076, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Gerlach
authors.forename: Alexander
authors.initials: A
authors.lastname: Steimle
authors.forename: Lea
authors.initials: L
authors.lastname: Krampen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Wittmann
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gronbach
authors.forename: Julia
authors.initials: J
authors.lastname: Geisel
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Autenrieth
authors.forename: Julia-Stefanie
authors.initials: JS
authors.lastname: Frick
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001439:Bacteroides / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D007093:Imidazoles / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D019013:CD40 Antigens; D016207:Cytokines; D007093:Imidazoles; D011725:Pyridines; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole