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.
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6 April 1998
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April 06 1998
Transgene Expression of bcl-xL Permits Anti-immunoglobulin (Ig)–induced Proliferation in xid B Cells
Nanette Solvason,
Nanette Solvason
From the *Department of Immunology; the ‡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
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Wei Wei Wu,
Wei Wei Wu
From the *Department of Immunology; the ‡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
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Nisha Kabra,
Nisha Kabra
From the *Department of Immunology; the ‡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
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Fridjtof Lund-Johansen,
Fridjtof Lund-Johansen
From the *Department of Immunology; the ‡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
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Maria Grazia Roncarolo,
Maria Grazia Roncarolo
From the *Department of Immunology; the ‡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
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Timothy W. Behrens,
Timothy W. Behrens
From the *Department of Immunology; the ‡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
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Didier A.M. Grillot,
Didier A.M. Grillot
From the *Department of Immunology; the ‡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
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Gabriel Nunez,
Gabriel Nunez
From the *Department of Immunology; the ‡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
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Emma Lees,
Emma Lees
From the *Department of Immunology; the ‡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
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Maureen Howard
Maureen Howard
From the *Department of Immunology; the ‡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
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Nanette Solvason
From the *Department of Immunology; the ‡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
Wei Wei Wu
From the *Department of Immunology; the ‡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
Nisha Kabra
From the *Department of Immunology; the ‡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
Fridjtof Lund-Johansen
From the *Department of Immunology; the ‡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
Maria Grazia Roncarolo
From the *Department of Immunology; the ‡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
Timothy W. Behrens
From the *Department of Immunology; the ‡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
Didier A.M. Grillot
From the *Department of Immunology; the ‡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
Gabriel Nunez
From the *Department of Immunology; the ‡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
Emma Lees
From the *Department of Immunology; the ‡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
Maureen Howard
From the *Department of Immunology; the ‡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
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:[email protected]
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.
Received:
November 24 1997
Revision Received:
January 29 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (7): 1081–1091.
Article history
Received:
November 24 1997
Revision Received:
January 29 1998
Citation
Nanette Solvason, Wei Wei Wu, Nisha Kabra, Fridjtof Lund-Johansen, Maria Grazia Roncarolo, Timothy W. Behrens, Didier A.M. Grillot, Gabriel Nunez, Emma Lees, Maureen Howard; Transgene Expression of bcl-xL Permits Anti-immunoglobulin (Ig)–induced Proliferation in xid B Cells . J Exp Med 6 April 1998; 187 (7): 1081–1091. doi: https://doi.org/10.1084/jem.187.7.1081
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