title: Defects in acute responses to TLR4 in Btk-deficient mice result in impaired dendritic cell-induced IFN-γ production by natural killer cells.
abstract: This study defines a critical role for Btk in regulating TLR4-induced crosstalk between antigen presenting cells (APCs) and natural killer (NK) cells. Reduced levels of IL-12, IL-18 and IFN-γ were observed in Btk-deficient mice and ex vivo generated macrophages and dendritic cells (DCs) following acute LPS administration, whilst enhanced IL-10 production was observed. In addition, upregulation of activation markers and antigen presentation molecules on APCs was also impaired in the absence of Btk. APCs, by virtue of their ability to produce IL-12 and IL-18, are strong inducers of NK-derived IFN-γ. Co-culture experiments demonstrate that Btk-deficient DCs were unable to drive wild-type or Btk-deficient NK cells to induce IFN-γ production, whereas these responses could be restored by exogenous administration of IL-12 and IL-18. Thus Btk is a critical regulator of APC-induced NK cell activation by virtue of its ability to regulate IL-12 and IL-18 production in response to acute LPS administration.
authors.affiliation: Molecular and Cellular Therapeutics and RSCI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Joan
authors.initials: J
authors.lastname: Ní Gabhann
authors.forename: Shaun
authors.initials: S
authors.lastname: Spence
authors.forename: Claire
authors.initials: C
authors.lastname: Wynne
authors.forename: Siobhán
authors.initials: S
authors.lastname: Smith
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Byrne
authors.forename: Barbara
authors.initials: B
authors.lastname: Coffey
authors.forename: Kevin
authors.initials: K
authors.lastname: Stacey
authors.forename: Adrien
authors.initials: A
authors.lastname: Kissenpfennig
authors.forename: Jim
authors.initials: J
authors.lastname: Johnston
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Jefferies
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase