The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/4/1081/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 7, April 6, 1998 1081-1091

Articles

Transgene Expression of bcl-xL Permits Anti-immunoglobulin (Ig)–induced Proliferation in xid B Cells

Nanette Solvason*, Wei Wei Wu*, Nisha Kabra*, Fridjtof Lund-Johansen{ddagger}, Maria Grazia Roncarolo{ddagger}, Timothy W. Behrens||, Didier A.M. Grillot, Gabriel Nunez, Emma Lees§, and Maureen Howard*

From the * Department of Immunology; the {ddagger} Department of Human Immunology; and the § Department of Cell Signaling, DNAX Research Institute, Palo Alto, California 94304; the || Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455; the University of Michigan Medical School, Ann Arbor, Michigan 48109

Mutations in the tyrosine kinase, Btk, result in a mild immunodeficiency in mice (xid). While B lymphocytes from xid mice do not proliferate to anti-immunoglobulin (Ig), we show here induction of the complete complement of cell cycle regulatory molecules, though the level of induction is about half that detected in normal B cells. Cell cycle analysis reveals that anti-Ig stimulated xid B cells enter S phase, but fail to complete the cell cycle, exhibiting a high rate of apoptosis. This correlated with a decreased ability to induce the anti-apoptosis regulatory protein, Bcl-xL. Ectopic expression of Bcl-xL in xid B cells permitted anti-Ig induced cell cycle progression demonstrating dual requirements for induction of anti-apoptotic proteins plus cell cycle regulatory proteins during antigen receptor mediated proliferation. Furthermore, our results link one of the immunodeficient traits caused by mutant Btk with the failure to properly regulate Bcl-xL.

Address correspondence to Nanette Solvason at her current address, Anergen, Inc., 301 Penobscot Dr., Redwood City, CA. 94063. Phone: 650-361-8901; Fax: 650-361-8958; E-mail:nsolvason{at}anergen.com

1Abbreviations used in this paper: BrdU, bromodeoxyuridine; Btk, Bruton's tyrosine kinase; cdc, cell division cycle; cdk, cyclin-dependent kinases; PI, propidium iodide; Rb, retinoblastoma gene; XLA, X-linked agammaglobulinemia.

DNAX Research Institute is fully funded by Schering Plough.


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