Tracking the response of Xid B cells in vivo: TI-2 antigen induces migration and proliferation but Btk is essential for terminal differentiation.
X-linked immunodeficient (Xid) mice carry a Bruton's tyrosine kinase (Btk) mutation and exhibit a selective failure to produce antibodies against bacterial capsular polysaccharides. Studies in vitro point to a fundamental survival defect of Xid B cells after receptor cross-linking by thymus-independent type-2 (TI-2) antigen because B cells undergo apoptosis without proliferating. We describe results from a novel model, which we have used to investigate the impact of the Xid mutation on migration, proliferation and differentiation of B cells after polysaccharide immunization in vivo. Immunoglobulin knock-in mice, in which a large proportion of B cells express transgene-encoded receptors specific for (4-hydroxy-3-nitrophenyl)-acetyl (NP), were crossed with CBA/N mice. The male progeny contain NP-specific Xid B cells, while the female progeny contain NP-specific B cells with normal Btk. After immunization with the TI-2 antigen NP-Ficoll, NP-specific Xid B cells migrate to the T zones and proliferate. Despite transient up-regulation of blimp-1 and survival beyond the time when terminal differentiation is normally underway, Btk-defective B cells fail to differentiate to plasmablasts or germinal center cells. CD40 ligation partially restores their ability to form plasma cells in response to TI-2 antigen.
Vinuesa
C G
CG
Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston, GB.
Sunners
Y
Y
Pongracz
J
J
Ball
J
J
Toellner
K M
KM
Taylor
D
D
MacLennan
I C
IC
Cook
M C
MC
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000955:Antigens, T-Independent / Q000276:immunology*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009596:Nitrophenols / Q000276:immunology; D010641:Phenotype; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D014960:X Chromosome / Q000235:genetics
D000906:Antibodies; D000955:Antigens, T-Independent; D019013:CD40 Antigens; D009596:Nitrophenols; C513258:Prdm1 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse