XID AFFECTS EVENTS LEADING TO B-CELL CYCLE ENTRY

X-linked agammaglobulinemia patients and X-linked immunodeficient (rid ) mice possess mutations in the Bruton's tyrosine kinase (Btk kinase) gene and display defects in B cell development and activation by sig c ross-linking. Btk is an early activation kinase in sig-cross-linked B cells. xid does not ablate Btk protein kinase activity, and immediate signal transduction events, such as tyrosine phosphorylation, occur in sig-activated rid B cells. These cells do not subsequently progress i nto cell division and have a high rate of apoptosis, which has been sh own to correlate with an absence of sig-mediated induction of the bcl- x(L) protein. To establish the point where Btk activity is critical fo r progression beyond immediate signaling, we examined early and late e vents in sig-cross-linked rid B cells. Induction of proto-oncogenes an d nuclear factors occurred normally in rid cells. However, induction o f cyclins and increased GAPDH mRNA was not observed in rid cells. Degr adation of the cyclin inhibitor p27(Kip1) occurred normally in rid cel ls. After 24 h of culture with anti-mu, the remaining live, nonapoptot ic rid cells were enlarged, viable, and primed for subsequent stimulat ion by LPS. Our data suggest that the Btk kinase is not essential for several, G(1) events and that the failure of sig-activated rid B cells to enter cell cycle correlates with a defect of cyclin induction; Mor eover, these data suggest that Btk is important not only for immediate events following B cell activation and control of apoptosis but also for subsequent events leading to cyclin activation.