Affinity selection of immunoglobulins

Naive B cells (B cells which have not yet encountered antigen) localize to B cell follicles due to the activation of CXCR5 on their surfaces by CXC13 secreted by FDCs; after activation and cognate T cell help, the GC B cell reaction is initiated (reviewed in Haberman et al. 2019, Victora and Nussenzweig 2022). Tonic signaling by the B cell receptor (BCR) is important for basal B cell survival, thus B cells with non‑functional receptors are lost (reviewed in Inoue et al. 2024). Within the germinal center, affinity of BCRs for antigen is tested by interaction with antigen located on the surface of FDCs in immune complexes that contain immunoglobulin‑complexed antigen bound to FCGR2B (Fc gamma receptor IIB) or bound via complement proteins to CR1 and CR2 (Yoshida et al. 1993, Fang et al. 1998, Fischer et al. 1998, Qin et al. 2000, El Shikh et al. 2006, Heesters et al. 2013, reviewed in Carroll 1998, Heesters et al. 2014, Papa and Viuesa 2018). FDCs maintain undegraded immune complexes for long periods of time, perhaps months, and cycle them between endosomal compartments and the cell surface (reviewed in Heesters et al. 2014).

The immune synapse between B cells and FDCs is an unusual structure in which the BCR is distributed in small clusters at the periphery of the contact zone rather than in a large cluster at the center (Nowosad et al. 2016, reviewed in Tolar 2017, Papa and Viuesa 2018, Inoue et al. 2024). B cells that express high affinity BCRs are able to remove antigen‑coated sections of membrane from FDCs through the action of non-muscle myosin IIa (MYH9) on the actin cytoskeleton within the B cell that invaginates the FDC membrane and pinches it off (Batista et al. 2001, Fleire et al. 2006, Natkanski et al. 2013, Nowosad et al. 2016, reviewed in Tolar 2017, Papa and Vinuesa 2018). Crosslinking of BCRs by antigen at this stage induces BCR signaling that maintains survival of B cells (reviewed in Inoue et al. 2024). B cells are professional antigen‑presenting cells that endocytose the BCR:antigen complex, proteolyze the antigen, and present antigen peptides on MHC II complexes to Tfh cells.

The presented antigen peptides interact with the T cell receptor (TCR) and MHC II interacts with CD4 on the Tfh cell, which then provides help in the form of secreted cytokines, notably IL4 and IL21, and CD40L that prevent apoptosis of the B cell (Ding et al. 2013, Weinstein et al. 2016, Gonzalez et al. 2018, Luo et al. 2023, reviewed in Crotty 2019, Qi et al. 2023) and cause the B cell to transit to the dark zone for proliferation and AICDA‑induced somatic hypermutation of immunoglobulin variable regions (reviewed in Pilzecker and Jacobs 2019, Yu 2022, Hao et al. 2024). Following hypermutation, the pre‑existing, unmutated immunoglobulin on the B cell is degraded and replaced by the mutated immunoglobulin before the B cell leaves the dark zone to re‑enter the light zone. The selection process is then repeated with the mutated immunoglobulin in order to optimize affinity for antigen.