Compartments and Connections Within the Germinal Center

Abstract

Protective high affinity antibody responses emerge through an orchestrated developmental process that occurs in germinal centers (GCs). While GCs have been appreciated since 1930, a wealth of recent progress provides new insights into the molecular and cellular dynamics governing humoral immunity. In this review, we highlight advances that demonstrate that fundamental GC B cell function, selection, proliferation and SHM occur within distinct cell states. The resulting new model provides new opportunities to understand the evolution of immunity in infectious, autoimmune and neoplastic diseases.

Keywords: B cell; T cell help; affinity maturation; epigenetics; germinal center; somatic hypermutation; tingible body macrophage; transcription.

Figure 1

Model of germinal center dynamics and compartmentalization. GC B cells progress through a series of molecular states compartmentalizing key functions to distinct spatial niches. (A) GC B cell selection occurs in the LZ. B cells entering the LZ from the DZd first attempt to capture antigen deposited on follicular dendritic cells (FDC). This is followed by antigen processing and presentation to T_FH cells in the context of MHC class II. Interactions between LZ B cells and T_FH determine if B cells are fated to differentiate into MBCs or PBs, undergo cyclic re-entry into the DZp, or initiate apoptosis. Cells selected for cyclic re-entry migrate to the DZp (B). We propose that B cells that initiate apoptosis in the LZ are cleared by TBMs in the DZp niche. Those cells that are successfully selected in the LZ, and therefore are not cleared by TBMs, undergo mitosis. (C) After one or more rounds of cell division, GC B cells transit to the DZd compartment where differentiative functions, such as SHM and replacing old BCRs with newly mutated BCRs, are proposed to occur. B cells that successfully complete processes in the DZd migrate to the LZ to undergo selection. Figure created with BioRender.com.