Development

The primary response to T cell-dependent Ag occurs in the T cell areas of secondary lymphoid organs and generates Ag-specific B cells which migrate into follicles and give rise to GCs. Newly formed GCs are oligoclonal, as, on average, each mature GC is derived from the colonization of no more than 1-3 B cell blasts. Ag-specific immigrant B cells gather around the Ag-holding cytoplasmic protrusions of FDCs and are interspersed with Ag-specific T lymphocytes. Cycling B cells in the dark areas of the GC (centroblasts) undergo somatic mutations of the VH and VL genes that generate Ab of optimal affinity. Point mutations accumulate in the VH and VL genes independently of the V region utilized or of self specificity and are preferentially localized in the complementarity-determining region (CDR)-encoding segments. Centroblasts transform into noncycling centrocytes that migrate towards the light zone of the GC, switch their Ig phenotype under the control of cytokines and are eliminated by apoptosis, unless further stimulated by additional signals. The specific Ag interaction with surface Ig is the main signal that prevents apoptosis as it ensures the specificity of the selection process. Additional signals delivered through the interaction of B cell CD40 with its ligand (CD40L) also prevent apoptosis as assessed by in vitro tests and in vivo observations on patients with CD40L deficiency (X-linked hyper-IgM syndrome) or on CD40L knockout mice. CD40L is expressed primarily by T cells, again reaffirming the T cell dependence of GC formation. Other less well defined antiapoptotic signals are delivered by other cells (FDCs, macrophages or B cells themselves) through CD40-CD40L interactions (FDCs express CD40L) and the stimulation of CD20, CD21 and CD38 molecules. All these stimuli prevent apoptosis by inducing the expression of Bcl-2 protein, a potent antidote to apoptosis. The majority of cells within the GC fail to express Bcl-2: proliferating centroblasts are Bcl-2 negative and only the centrocytes that have survived the whole molecular screening process of the GC become Bcl-2 positive and acquire the ability to survive. The GC-based screening program includes the prevention of autoimmune reactivity by inducing the apoptosis of self reacting B cells. Some censoring mechanisms that prevent the development of antiself reactions during the process of B cell selection in the GC have been partially elucidated. First, the exclusion of self Ag-binding B cells from the normal migration route into lymphoid follicles. Second, the exposure of self Ag-specific B cells to excess soluble Ag. Also, centrocytes exposed to CD40L upregulate the expression of Fas/CD95, a member of the tumor necrosis factor (TNF)-receptor (R) superfamily that transduces apoptotic signals to B cells upon interaction with activated T cells expressing CD95L. Thus, additional pathways to eliminate unwanted B cells may be controlled by T cells by means of the CD95/CD95L system.

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