Tracking the response of Xid B cells in vivo: Tl-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 bact erial capsular polysaccharides. Studies in vitro point to a fundamental sur vival defect of Xid B cells after receptor crosslinking by thymus-independe nt type-2 (TI-2) antigen because B cells undergo apoptosis without prolifer ating. We describe results from a novel model, which we have used to invest igate the impact of the Xid mutation on migration, proliferation and differ entiation of B cells after polysaccharide immunization in vivo. Immunoglobu lin 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. Afte r immunization with the TI-2 antigen NP-Ficoll, NP-specific Xid B cells mig rate to the T zones and proliferate. Despite transient up-regulation of bli mp-1 and survival beyond the time when terminal differentiation is normally underway, Btk-defective B cells fail to differentiate to plasmablasts or g erminal center cells. CD40 ligation partially restores their ability to for m plasma cells in response to TI-2 antigen.