Abstract
A hallmark of T cell–dependent immune responses is the progressive increase in the ability of serum antibodies to bind antigen and provide immune protection. Affinity maturation of the antibody response is thought to be connected with the preferential survival of germinal centre (GC) B cells that have acquired increased affinity for antigen via somatic hypermutation of their immunoglobulin genes. However, the mechanisms that drive affinity maturation remain obscure because of the difficulty in tracking the affinity-based selection of GC B cells and their differentiation into plasma cells. We describe a powerful new model that allows these processes to be followed as they occur in vivo. In contrast to evidence from in vitro systems, responding GC B cells do not undergo plasma cell differentiation stochastically. Rather, only GC B cells that have acquired high affinity for the immunizing antigen form plasma cells. Affinity maturation is therefore driven by a tightly controlled mechanism that ensures only antibodies with the greatest possibility of neutralizing foreign antigen are produced. Because the body can sustain only limited numbers of plasma cells, this “quality control” over plasma cell differentiation is likely critical for establishing effective humoral immunity.
Highlights
A major weapon used by the immune system to combat infection is the secretion of antibody molecules into bodily fluids
Evidence that germinal center (GC) might be connected with maturation of the serum antibody response was provided by the discovery that somatic hypermutation (SHM) of Ig genes occurs in GCs [6] and that rare mutant clones expressing B cell receptor for antigen (BCR) with increased affinity for the immunizing antigen preferentially survive there [4, 7]
Indirect evidence suggests that plasma cell differentiation of GC B cells may be more selective, with only those cells that exceed a threshold antigen affinity contributing to the antibody response [10, 11]
Summary
A major weapon used by the immune system to combat infection is the secretion of antibody molecules into bodily fluids. RESULTS AND DISCUSSION When SWHEL B cells are challenged with either high affinity (HELWT-SRBC) or low affinity (HEL3X-SRBC) antigen in CD45.1 congenic recipient mice, similar frequencies of donor-derived (CD45.2+) GC B cells are produced at over the first 15 d of the response [14], and these cells undergo equivalent rates of class switch recombination to IgG1 (Fig. 1 A).
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