Exploring how the germinal center cellular program promotes efficient affinity maturation

High affinity antibodies develop in germinal centers (GCs) through iterative rounds of somatic hypermutation and selection. Selection involves B cells competing for limiting T cell help; affinity-promoting mutations allow cells to acquire more antigen and present greater amounts of peptide-MHCII. How GC B cells deal with the unique demand of rapidly and repeatedly switching BCR specificity while ensuring selection occurs only on the basis only their newest specificity is not known and will be a major focus of this fellowship. We will generate new genetic tools to allow us to temporally tag and fate-map receptors and MHCII proteins, thereby addressing how and when old molecules are replaced. We will test the hypothesis that antigen-presentation is favored at particular cellular stages, and peptide-MHC complexes degraded at others. The molecular mechanisms controlling this will be examined. GC B cell behavior is determined in large part by an intrinsic cellular program that involves a ti mer component to govern switching between states - we will begin a longer-term quest of understanding how this is regulated by probing changes that occur within individual cells as they transition through the program. This work will help elucidate how quality antibodies are generated during infections and after immunizations.