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Garnett Kelsoe
University of Maryland
School of Medicine
Baltimore, MD

Antigen-Driven V(D)J Recombination in Germinal Center Lymphocytes

The antibody response begins when antigen-specific B and T lymphocytes make contact and proliferate in the T cell zones of secondary lymphoid tissues. These activated B cells become committed to differentiation into short-lived plasmacytes or participation in the germinal center (GC) reaction. Both pathways accept cells with identical receptor affinities and VDJ gene rearrangements. In naive mice, GCs first appear at day 4 postimmunization; their cellular peak is reached by day 10-12, and the GC reaction is usually over in 4-5 weeks. Early on, the GC becomes organized into a dark zone of rapidly-dividing, mIg- centroblasts and a light zone containing the majority of the T cell population and nondividing, mIg+ centrocytes.

V(D)J hypermutation is active in GCs and diversifies Ig rearrangements. Mutant GC B cells undergo selection, interspersed with periods of mutation and proliferation, as the GC becomes a microcosm of darwinian selection. A subset of GC B cells – those with very low affinity for the immunogen – reactivate the V(D)J recombinase and initiate secondary V-to-J rearrangements in the L-chain loci. These cells also transcribe the g5 and V-pre B genes. The significance of this antigen-dependent Ig remodeling is not yet known, but if B cells bearing secondary V(D)J rearrangements leave GCs, the common notion of clonal selection must be rethought.