Visualizing antibody affinity maturation in germinal centers

Diversity reigns in antibody responses During the course of an immune response, B cells specific for an invading pathogen divide. The antibodies they produce increase in affinity via somatic mutation in specialized lymph node structures called germinal centers. Tas et al. used multiphoton microscopy and sequencing to determine how different B cell clones compete with one another within mouse germinal centers. Multiple B cell clones can seed individual germinal centers, and germinal centers lose diversity at disparate rates. Such heterogeneity suggests that manipulating minor clonal populations to gain an advantage during vaccination may one day be possible. Science, this issue p. 1048 Germinal center B cells are clonally diverse, and the antibodies these cells express mature at different rates. Antibodies somatically mutate to attain high affinity in germinal centers (GCs). There, competition between B cell clones and among somatic mutants of each clone drives an increase in average affinity across the population. The extent to which higher-affinity cells eliminating competitors restricts clonal diversity is unknown. By combining multiphoton microscopy and sequencing, we show that tens to hundreds of distinct B cell clones seed each GC and that GCs lose clonal diversity at widely disparate rates. Furthermore, efficient affinity maturation can occur in the absence of homogenizing selection, ensuring that many clones can mature in parallel within the same GC. Our findings have implications for development of vaccines in which antibodies with nonimmunodominant specificities must be elicited, as is the case for HIV-1 and influenza.