Relaxed negative selection in germinal centers and impaired affinity maturation in bcl-xL transgenic mice.
The role of apoptosis in affinity maturation was investigated by determining the affinity of (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific antibody-forming cells (AFCs) and serum antibody in transgenic mice that overexpress a suppressor of apoptosis, Bcl-xL, in the B cell compartment. Although transgenic animals briefly expressed higher numbers of splenic AFCs after immunization, the bcl-xL transgene did not increase the number or size of germinal centers (GCs), alter the levels of serum antibody, or change the frequency of NP-specific, long-lived AFCs. Nonetheless, the bcl-xL transgene product, in addition to endogenous Bcl-xL, reduced apoptosis in GC B cells and resulted in the expansion of B lymphocytes bearing VDJ rearrangements that are usually rare in primary anti-NP responses. Long-lived AFCs bearing these noncanonical rearrangements were frequent in the bone marrow and secreted immunoglobulin G(1) antibodies with low affinity for NP. The abundance of noncanonical cells lowered the average affinity of long-lived AFCs and serum antibody, demonstrating that Bcl-xL and apoptosis influence clonal selection/maintenance for affinity maturation.
Takahashi
Y
Y
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore 21201, USA.
Cerasoli
D M
DM
Dal Porto
J M
JM
Shimoda
M
M
Freund
R
R
Fang
W
W
Telander
D G
DG
Malvey
E N
EN
Mueller
D L
DL
Behrens
T W
TW
Kelsoe
G
G
D000818:Animals; D000906:Antibodies / Q000097:blood; D000915:Antibody Affinity / Q000235:genetics*; D000917:Antibody Formation / Q000235:genetics; D000921:Antibody-Producing Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D013154:Spleen; D019076:Transgenes / Q000276:immunology; D051020:bcl-X Protein
D000906:Antibodies; C494812:Bcl2l1 protein, mouse; D007135:Immunoglobulin Variable Region; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein