Relaxed Negative Selection in Germinal Centers and Impaired Affinity Maturation in bcl-xL Transgenic Mice

Author:

Takahashi Yoshimasa1,Cerasoli Douglas M.1,Dal Porto Joseph M.1,Shimoda Michiko1,Freund Robert1,Fang Wei2,Telander David G.2,Malvey Erika-Nell2,Mueller Daniel L.2,Behrens Timothy W.2,Kelsoe Garnett3

Affiliation:

1. From the Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201

2. Center for Immunology, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455

3. Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710

Abstract

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 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-xL and apoptosis influence clonal selection/maintenance for affinity maturation.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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