Optimality of mutation and selection in germinal centers.
The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the approximately 100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understanding of the functions of germinal centers.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
Jingshan
J
Zhang
Eugene I
EI
Shakhnovich
D000465:Algorithms; D000818:Animals; D000915:Antibody Affinity; D001402:B-Lymphocytes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D030562:Databases, Protein; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D006801:Humans; D018448:Models, Immunological; D015233:Models, Statistical; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D012641:Selection, Genetic; D013154:Spleen