Defects in acute responses to TLR4 in Btk -deficient mice result in impaired dendritic cell-induced IFN-γ production by natural killer cells

• Published in: Clinical immunology (Orlando, Fla.) Vol. 142; no. 3; pp. 373 - 382
• Main Authors: Ní Gabhann, Joan, Spence, Shaun, Wynne, Claire, Smith, Siobhán, Byrne, Jennifer C, Coffey, Barbara, Stacey, Kevin, Kissenpfennig, Adrien, Johnston, Jim, Jefferies, Caroline A
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.03.2012; Elsevier
• Subjects: Allergy and Immunology; Animals; Antigen presenting cells; Biological and medical sciences; Btk; Cells, Cultured; Coculture Techniques; Dendritic Cells - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; IFN-γ; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Killer Cells, Natural - immunology; Mice; Mice, Inbred C57BL; Natural killer cells; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - immunology; TLRs; Toll-Like Receptor 4 - immunology; Btk; Antigen presenting cells; IFN-γ; Natural killer cells; TLRs; Dendritic cell; Toll like receptor 4; Acute; Deficiency; Rodentia; Toll like receptor; Biosynthesis; Natural killer cell; Vertebrata; Bruton tyrosine kinase; Mammalia; Immunology; Mouse; Antigen presenting cell; Animal; Gamma interferon
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2011.12.009

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.