TY - JOUR
T1 - Relaxed negative selection in germinal centers and impaired affinity maturation in bcl-x(L) transgenic mice
AU - Takahashi, Yoshimasa
AU - Cerasoli, Douglas M.
AU - Dal Porto, Joseph M.
AU - Shimoda, Michiko
AU - Freund, Robert
AU - Fang, Wei
AU - Telander, David G.
AU - Malvey, Erika Nell
AU - Mueller, Daniel L
AU - Behrens, Timothy W.
AU - Kelsoe, Garnett
PY - 1999/8/2
Y1 - 1999/8/2
N2 - 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-x(L), in the B cell compartment. Although transgenic animals briefly expressed higher numbers of splenic AFCs after immunization, the bcl-x(L) 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-x(L) transgene product, in addition to endogenous bcl-x(L), 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 G1 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-x(L) and apoptosis influence clonal selection/maintenance for affinity maturation.
AB - 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-x(L), in the B cell compartment. Although transgenic animals briefly expressed higher numbers of splenic AFCs after immunization, the bcl-x(L) 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-x(L) transgene product, in addition to endogenous bcl-x(L), 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 G1 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-x(L) and apoptosis influence clonal selection/maintenance for affinity maturation.
KW - Affinity maturation
KW - Apoptosis
KW - Bcl-x(L)
KW - Clonal selection
KW - Germinal center
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U2 - 10.1084/jem.190.3.399
DO - 10.1084/jem.190.3.399
M3 - Article
C2 - 10430628
AN - SCOPUS:0033517153
SN - 0022-1007
VL - 190
SP - 399
EP - 409
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
ER -