Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing.
Control of integrin-mediated adhesion and migration by chemokines plays a critical role in B cell development, differentiation, and function; however, the underlying signaling mechanisms are poorly defined. Here we show that the chemokine SDF-1 induced activation of Bruton's tyrosine kinase (Btk) and that integrin-mediated adhesion and migration in response to SDF-1 or CXCL13, as well as in vivo homing to lymphoid organs, was impaired in Btk-deficient (pre-)B cells. Furthermore, SDF-1 induced tyrosine phosphorylation of Phospholipase Cgamma2 (PLCgamma2), which, unlike activation of the migration regulatory GTPases Rac or Rap1, was mediated by Btk. PLCgamma2-deficient B cells also exhibited impaired SDF-1-controlled migration. These results reveal that Btk and PLCgamma2 mediate chemokine-controlled migration, thereby providing insights into the control of B cell homeostasis, trafficking, and function, as well as into the pathogenesis of the immunodeficiency disease X-linked agammaglobulinemia (XLA).
de Gorter
David J J
DJ
Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Beuling
Esther A
EA
Kersseboom
Rogier
R
Middendorp
Sabine
S
van Gils
Janine M
JM
Hendriks
Rudolf W
RW
Pals
Steven T
ST
Spaargaren
Marcel
M
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology; D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; D018925:Chemokines / Q000276:immunology*; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016023:Integrins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D051966:Phospholipase C gamma / Q000276:immunology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*
C515255:CXCL12 protein, human; C110663:CXCL13 protein, human; D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016023:Integrins; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D051966:Phospholipase C gamma