Dynamics of B cells in germinal centres

Abstract

The germinal centre (GC) of lymphoid organs is the microenvironment in which antigen-activated B cells diversify their immunoglobulin genes by somatic hypermutation (SHM) to generate high-affinity antibodies. A subset of the cells also undergoes class-switch recombination to generate antibodies with specialized effector functions. Early in an immune response, antigen-stimulated B cells form long-lived interactions with antigen-specific T cells at the border between the B cell zone and the T cell zone or the interfollicular region to become fully activated. Antigen-activated B cells and T cells are committed to differentiate into GC B cells and T follicular helper cells (T_FH cells), respectively, outside of the follicle. Migration into the follicle is facilitated by B cell lymphoma 6 (BCL-6), which is the master transcriptional regulator of GC B cells. One day after T_FH cells have moved into the follicle, GC precursor B cells migrate from the border between the B cell zone and the T cell zone or the interfollicular region into the centre of the follicle to form an early GC. The B cells differentiate into blasts and, over the next several days, rapidly divide and begin to fill the centre of the follicle until they have formed a mature GC that is polarized into two microenvironments known as the dark and light zones. Dark zone B cells, which are GC B cells that undergo active SHM, are programmed to proliferate extremely rapidly and thereby to generate a large number of immunoglobulin mutations in a short time. Dark zone B cells differentiate into light zone B cells, at which stage mutants expressing high-affinity antibodies are selected and instructed to either recirculate to the dark zone to undergo further rounds of SHM or to differentiate into memory B cells or plasma cells. Light zone B cells capture antigen via the B cell receptor (BCR) and present the processed antigen on MHC complexes to T_FH cells. Higher BCR affinity is directly associated with greater antigen capture and leads to a higher density of peptide–MHC complex presentation on the surface of the B cell. This results in the greatest share of T cell help, which in turn drives selection. Evidence suggests that the transcription factors MYC and the nuclear factor-κB subunit REL are essential for the maintenance of the GC reaction as they 'license' antigen-selected light zone B cells to recirculate to the dark zone. Inhibition of the terminal differentiation of GC B cells is controlled by multiple mechanisms that include both transcriptional and non-transcriptional regulation.