Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells.
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.
Solvason
N
N
Department of Immunology, DNAX Research Institute, Palo Alto, California 94304, USA. nsolvason@anergen.com
Wu
W W
WW
Kabra
N
N
Lund-Johansen
F
F
Roncarolo
M G
MG
Behrens
T W
TW
Grillot
D A
DA
Nunez
G
G
Lees
E
E
Howard
M
M
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology; D002470:Cell Survival; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics*; D007136:Immunoglobulins / Q000276:immunology*; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic / Q000276:immunology*; D010641:Phenotype; D011494:Protein Kinases / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics*; D013154:Spleen / Q000166:cytology; D051020:bcl-X Protein
D015703:Antigens, CD; C494812:Bcl2l1 protein, mouse; D007136:Immunoglobulins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D001973:Bromodeoxyuridine