Regulation of the Germinal Center Response

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.

Intrinsic defects in lymph node stromal cells underpin poor germinal center responses during aging

“…The generation of lasting protective immunity requires the production of long-lived plasma cells that secrete high affinity class-switched antibodies 6 . Plasma cells are the ultimate output of the germinal center (GC), a specialized immune response that forms in secondary lymphoid organs 7 . The GC reaction requires the concerted efforts of many different cell types that must be coordinated in time and space: B cells, T follicular helper (Tfh) cells, dendritic cells and macrophages are brought together upon a network of specialized stromal cells that provide migratory cues that direct cells to, and within, the GC 8 .The GC is a polarized structure with two functionally distinct compartments known as light and dark zones 9,10 .…”

“…To do this, GC B cells move to the light zone where they can receive help from a specialized subset of CD4 + T cells, Tfh cells 11 . GC B cells that received help from Tfh cells then migrate back to the dark zone and either undergo further rounds of proliferation and mutation or differentiate into memory B cells or long-lived antibody-secreting cells that exit the GC 7 .…”

Arhgap25deficiency leads to decreased numbers of peripheral blood B cells and defective germinal center reactions

“…The CXCR4-CXCL12 interaction is of central importance in the GC reaction (23, 27, 28), and we have previously shown that ARHGAP25 regulates the strength of response to CXCR4 signaling in hematopoietic stem and progenitor cells (21). Furthermore, CXCL12 is highly expressed in the GC DZ, where we found more B cells in Arhgap25 -/- mice.…”

Revisiting the Interaction of γδ T-Cells and B-Cells

“…The GC reaction plays an important role in humoral immunity, as B-cells with the highest affinity to GC-contained antigens are selected to become plasma cells that produce high-affinity antibodies or memory B-cells [72][73][74]. GCs are formed in secondary lymphoid organs at different time points.…”