![]() DEC-205 is an endocytic receptor that is primarily expressed in dendritic cells but also in B cells and directs captured Ag to Ag-processing compartments ( 23). This selection mechanism is further supported by studies using a DEC-205-antibody-based Ag delivery approach ( 22). Together with a mathematical simulation model ( 20), these findings support that T cells are a limiting factor and positive selection can occur in a T cell-driven selection mechanism ( 12, 21). These observations suggest that interactions between GC-B cells and TFHs are strictly controlled and therefore GC-B cells may compete for cognate T cell help. Moreover, only a limited proportion of T cells in GCs appear to actively interact with GC-B cells that are significantly more numerous than TFHs within the time window of confocal microscopic analysis ( 12, 18). Contact duration between cognate T cells and GC-B cells is shorter than that between T cell and Ag-activated B cells before GC formation ( 12, 18, 19). For promoting efficient positive selection, recycling GC-B cells reset their BCRs and MHCII before reentering the LZ ( 16, 17). Higher-affinity GC-B cells more effectively receive helper signals from TFHs because they acquire more Ag, present pMHCII at higher levels and thereby induce greater TFH activation, this is in line with studies from early B cell responses in vivo ( 14) and in vitro ( 15). LZ-B cells capture FDC-bound Ags through their BCRs, process and present them in the form of pMHCII and signals downstream of BCR-Ag engagement allow survival. In the currently favored model, positive selection occurs in an affinity-dependent manner ( 12, 13). cMyc is induced upon positive selection and its expression effectively defines positively selected GC-B cells ( 7, 8). In response to signals from BCR engagement and TFHs, a fraction of LZ-B cells are positively selected and results in evasion of apoptosis partially in a microRNA-155-dependent manner ( 10, 11). In this review, we summarize and discuss studies illustrating how positive selection of GC-B cells are triggered, what molecular and cellular events that GC-B cells undergo during the process of positive selection, and how B cell fate decisions are coordinated during positive selection.Ĭurrent Models for Affinity-Dependent Positive Selection Eventually, GC reactions produce high-affinity antibody secreting plasma cells (PCs) and memory-B cells (MBCs). GC-B cells undergo iterative rounds of mutation and selection through a migration cycle between LZ and DZ. cMyc + GC-B-cells in the LZ re-start the cell cycle and travel to the DZ for further cell division ( 7– 9). These positively selected LZ-B cells induce cMyc, a critical regulator for GC maintenance and proliferation, and cMyc positivity transiently marks “licensed” GC-B cells ( 7, 8). ![]() B cell receptor (BCR) binding of Ag by LZ-B cells results in internalization of BCR-Ag and subsequent presentation of Ag in the form of Ag-specific-peptide-major histocompatibility II (pMHCII), which enables them to receive help from T follicular helper cells (TFHs). LZ-B cells retrieve Ag on follicular dendritic cells (FDCs) that can uniquely retain and display Ag in the form of immune complex (ICs) ( 6). In the LZ, GC-B cells are selected in an Ag and T cell-dependent manner. SHM is mediated by activation-induced cytidine deaminase (AID) ( 5) and occurs in the DZ where GC-B cells extensively proliferate. GCs include two distinct regions, light zone (LZ) and dark zone (DZ) ( 4). The process of increasing antibody affinity is known as affinity maturation ( 1, 2) and results from somatic hypermutation (SHM) of immunoglobulin (Ig) genes in GC-B cells and clonal selection ( 3). This specialized microstructure transiently forms within the B cell follicles of secondary lymphoid organs during the course of T cell-dependent immune responses. Germinal centers (GCs) are sites where antibody affinity for the antigen (Ag) is improved and Ag-activated B cells differentiate, hence they are important for host defense and clearance of exogenous pathogens.
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