Abstract
The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity. However, this mutation process can also be dangerous, as it can create autoreactive clones that can cause autoimmunity. Because of this, regulation of GC reactions is critical to ensure high affinity antibody production and to enforce self-tolerance by avoiding emergence of autoreactive B cell clones. A productive GC response requires the collaboration of multiple cell types. The stromal cell network orchestrates GC cell dynamics by controlling antigen delivery and cell trafficking. T follicular helper (Tfh) cells provide specialized help to GC B cells through cognate T-B cell interactions while Foxp3+ T follicular regulatory (Tfr) cells are key mediators of GC regulation. However, regulation of GC responses is not a simple outcome of Tfh/Tfr balance, but also involves the contribution of other cell types to modulate the GC microenvironment and to avoid autoimmunity. Thus, the regulation of the GC is complex, and occurs at multiple levels. In this review we outline recent developments in the biology of cell subsets involved in the regulation of GC reactions, in both secondary lymphoid tissues, and Peyer's patches (PPs). We discuss the mechanisms which enable the generation of potent protective humoral immunity whilst GC-derived autoimmunity is avoided.
Highlights
Reviewed by: Betty Diamond, Feinstein Institute for Medical Research, United States Oliver Bannard, University of Oxford, United Kingdom
follicular dendritic cells (FDCs) and T follicular helper (Tfh) cells are critical for the positive selection of centrocytes, while T follicular regulatory (Tfr) cells are thought to regulate the output of the germinal center (GC) response [3]
Tfr cells specialize in the regulation of the GC response by directly modulating Tfh cell proliferation, B cell metabolism and cytokines secreted by Tfh cells in secondary lymphoid organs
Summary
Within GCs, B cells undergo somatic hypermutation (SHM) of the genes encoding their B cell receptor (BCR) Because this mutational process is random, mutated B cells require selection to ensure that only B cells bearing a BCR with an improved affinity for antigen differentiate into long-lived antibody secreting plasma cells and memory B cells [3]. FDCs and Tfh cells are critical for the positive selection of centrocytes, while Tfr cells are thought to regulate the output of the GC response [3] Together, these processes culminate in the emergence of longlived antibody secreting plasma cells and memory B cells whose BCRs bind antigen with high affinity. These effector cells are able to provide protection against subsequent infection, in some cases providing life-long immunity against particular pathogens
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