Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses

Antibody affnity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and selection. Selection involves B cells competing for T cell help based on the amount of antigen they capture and present on their MHC class II (MHC II) proteins. How GC B cells are able to rapidly and repeatedly transition between mutating their B cell receptor genes and then being selected shortly after is not known. We report that MHC II surface levels and degradation are dynamically regulated in GC B cells. Through ectopic expression of a photoconvertible MHC II-mKikGR chimeric gene, we found that individual GC B cells differed in the rates of MHC II protein turnover. Fluctuations in surface MHC II levels were dependent on ubiquitination and the E3 ligase March1. Increases in March1 expression in centroblasts correlated with decreases in surface MHC II levels, whereas CD83 expression in centrocytes helped to stabilize MHC II at that stage. Defects in MHC II ubiquitination caused GC B cells to accumulate greater amounts of a specifc peptide–MHC II (pMHC II), suggesting that MHC II turnover facilitates the replacement of old complexes. We propose that pMHC II complexes are periodically targeted for degradation in centroblasts to favor the presentation of recently acquired antigens, thereby promoting the fdelity and effciency of selection