title: Tyrosine kinase Btk is required for NK cell activation.
abstract: Bruton tyrosine kinase (Btk) is not only critical for B cell development and differentiation but is also involved in the regulation of Toll-like receptor-triggered innate response of macrophages. However, whether Btk is involved in the regulation of natural killer (NK) cell innate function remains unknown. Here, we show that Btk expression is up-regulated during maturation and activation of mouse NK cells. Murine Btk(-/-) NK cells have decreased innate immune responses to the TLR3 ligand, with reduced expressions of IFN-γ, perforin, and granzyme-B and decreased cytotoxic activity. Furthermore, Btk is found to promote TLR3-triggered NK cell activation mainly by activating the NF-κB pathway. Poly(I:C)-induced NK cell-mediated acute hepatitis was observed to be attenuated in Btk(-/-) mice or the mice with in vivo administration of the Btk inhibitor. Correspondingly, liver damage was aggravated in Btk(-/-) mice after the adoptive transfer of Btk(+/+) NK cells, further indicating that Btk-mediated NK cell activation contributes to TLR3-triggered acute liver injury. Importantly, reduced TLR3-triggered activation of human NK cells was observed in Btk-deficient patients with X-linked agammaglobulinemia, as evidenced by the reduced IFN-γ, CD69, and CD107a expression and cytotoxic activity. These results indicate that Btk is required for activation of NK cells, thus providing insight into the physiological significance of Btk in the regulation of immune cell functions and innate inflammatory response.
authors.affiliation: Translational Medicine Center, Changzheng Hospital, Shanghai 200433, China. baoyan@yahoo.cn
authors.forename: Yan
authors.initials: Y
authors.lastname: Bao
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Han
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.forename: Huanxing
authors.initials: H
authors.lastname: Han
authors.forename: Yinping
authors.initials: Y
authors.lastname: Liu
authors.forename: Yu-Lung
authors.initials: YL
authors.lastname: Lau
authors.forename: Wenwei
authors.initials: W
authors.lastname: Tu
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D019264:Adoptive Transfer; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D015151:Immunoblotting; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D011070:Poly I-C / Q000633:toxicity; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D000077329:Agammaglobulinaemia Tyrosine Kinase; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D053804:Granzymes; D007371:Interferon-gamma; D037181:Lectins, C-Type; D052118:Lysosomal-Associated Membrane Protein 1; D054353:Perforin; D011070:Poly I-C; D011505:Protein-Tyrosine Kinases; D051196:Toll-Like Receptor 3; D000099192:CD69 Antigens; C000625949:BTK protein, human; C000625951:Btk protein, mouse