Biology Reference
In-Depth Information
expressing T cells in the absence of potent BCR triggering, or asynchronous
signaling through CD95, CD40, and BCR (Cleary et al., 1995). However, data
obtained in genetically modi®ed mice are not consistent with major roles for
Bcl-2 and Fas in a½nity maturation, but instead suggest that Bcl-2 facilitates
the survival of autoreactive B cells in the periphery (Smith et al., 1994, 1995). In
contrast, a½nity maturation seems to be controlled by Bcl-
xL
: bcl-xl transgene
expression increases the frequency of B cells bearing VDJ rearrangements en-
coding low-a½nity Ab, reduces the level of apoptosis in GC B cells, and fac-
ilitates a relaxed negative selection in GC (Takahashi et al., 1999). A½nity
maturation is therefore reduced in bcl-xl transgenic mice. The crosslinking of
BCR or CD40 extends the survival of centrocytes and up-regulates both Bcl-2
and Bcl-
xL
expression in mice and humans ( Liu et al., 1989; Tuscano et al.,
1996). Negative selection also takes place by receptor editing in centrocytes
(CD77
ÿ
, CD86
high
) re-expressing RAG-1 and RAG-2 proteins (Giachino et al.,
1998; Han et al., 1996). Selected centrocytes then di¨erentiate into Ag-speci®c
memory B cells and long-lived plasmablasts, producing IgM, G, A, and E with
a high a½nity for Ag. Plasmablasts and memory B cells then leave the follicle,
migrating to speci®c areas in which they complete their di¨erentiation.
Accurate synchronization is required between the circulation of lymphoid
cells and DC, the expression of molecules controlling cell-cell interactions or
interactions with the extracellular matrix, the expression of cytokine recep-
tors, and the production of cytokines to generate an e½cient humoral response.
Primary challenge with T-dependent Ag induces a strong GC response but a
weak extrafollicular response, whereas secondary challenge leads to a strong
extrafollicular response and a low GC response ( Kroese et al., 1990; Liu et al.,
1991). This re¯ects the location of the Ag targets: naive B cells giving rise to
GC founder cells during primary responses and memory B cells located in the
extrafollicular areas of lymphoid organs during secondary responses. It seems
likely that memory B cells rapidly transit through GC, in which they are re-
stimulated by Ag trapped on FDC. During the primary response, the size of the
GC rapidly increases with the entry of GC founder cells and their subsequent
clonal expansion, the expansion of the FDC network, and the entry of CXCR5-
expressing CD4
cells ( Forster et al., 1996). Recent data from studies of mice
have clearly shown that the colonization and the functioning of the GC require
interactions between B cells, FDC, and immune complexes bound to FDC
(Ngo et al., 1999). The normal development and function of the FDC net-
work depend on two major cytokines, lymphotoxin a1b2(LTa1b2) and tumor
necrosis factor-a ( TNF-a), probably produced by Ag-triggered B cells within
the GC (Futterer et al., 1998). Following Ag stimulation, the entry of B cells
into GC requires the local production of a recently identi®ed chemokine, B cell-
attracting chemokine 1 ( BCA-1), by FDC and DC (Cyster, 1999; Melchers et
al., 1999). GC enlargement decreases after 3±4 weeks of Ag stimulation: B-cell
expansion decreases, the e¨ector B cells (long-lived plasmablasts or memory
cells) leave the GC, the FDC network involutes, and most circulating Ag are
