Through a glass less darkly: Apoptosis and the germinal center response to antigen

The regulation of cell death is crucial for normal immune responses. Apoptosis is required for appropriate affinity-based recruitment of B cells into an immune response, for the normal expansion, contraction - and thereby selection - of B cells within germinal centers, and also for the normal expansion, contraction, and persistence of plasma cells, both extrafollicular and germinal center-derived. In this review, we focus on the intrinsic pathway of apoptosis, which is mediated by the interaction of pro- and anti-apoptotic members of the Bcl-2 family of proteins. Early, relatively crude studies using transgene-mediated over-expression of pro-survival proteins or germline-encoded loss of pro-apoptotic proteins demonstrated clearly the consequences of dysregulation of this apoptosis pathway on immunity. More recent studies have both been more targeted and extensive, meaning that a large number of Bcl-2 family members have been assessed for roles in immune regulation in a relatively precise manner. These studies are revealing a level of specialization in the use of the pro-survival proteins during immune responses, with several showing what appear to be stage-specific contributions. Lastly, we consider the involvement of Bcl-2 family proteins in the transformation of B cells at distinct stages of the response to antigen, comparing this involvement with that in the normal processes.