Vav proteins are required for B-lymphocyte responses to LPS.
B lymphocytes respond to bacterial lipopolysaccharide (LPS) through Toll-like receptor 4 (TLR4) and CD180 (previously called RP105). We show here that the responses of B lymphocytes to LPS require the function of the Vav family of guanine nucleotide exchange factors. Vav1-mutant mice generate defective humoral immunoglobulin G (IgG) responses following administration of low doses of LPS but respond normally to higher doses, while mice lacking both Vav1 and Vav2 manifest defective responses even after a high dose of LPS. Vav1/2-mutant B cells fail to divide extensively in vitro in response to LPS or CD180, while deficiency of Vav1 alone impairs CD180-but not LPS-driven proliferation. Likewise, activation of Akt (a PI3K [phosphatidylinositol 3-kinase] target) and phosphorylation of IkappaBalpha in response to CD180 or LPS required Vav1 and Vav2, while Vav1 deficiency led to defective responses to CD180. In addition, activation of ERK (extracellular signal regulated kinase) required Vav1 and Vav2 in response to CD180 but was Vav1 and vav2 independent in response to LPS. Induction of CD86 and CD25 by anti-CD180 also required Vav function, as did the induction of the anti-apoptotic protein Bcl-xL (B-cell leukemia XL). These data provide evidence for the function for the Vav proteins in regulating the responses of B cells to LPS.
Hebeis
Barbara
B
Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, United Kingdom.
Vigorito
Elena
E
Kovesdi
Dorottya
D
Turner
Martin
M
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D007074:Immunoglobulin G / Q000096:biosynthesis; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051020:bcl-X Protein
D015703:Antigens, CD; C494812:Bcl2l1 protein, mouse; D018797:Cell Cycle Proteins; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; C490500:Ly78 protein, mouse; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051567:Proto-Oncogene Proteins c-vav; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C496619:Vav1 protein, mouse; C490565:Vav2 protein, mouse; D051020:bcl-X Protein