Dynamic Regulation of Tfh Selection During the Germinal Center Reaction

The germinal center is a dynamic microenvironment wherein B cells expressing high affinity antibody variants produced by somatic hypermutation are selected for clonal expansion by limiting numbers of T follicular helper cells (1,2). Although much is known about the mechanisms that control B cell selection in the germinal center, far less is understood about the clonal behavior of the T follicular helper cells that regulate this process. Here we report on the dynamic behavior of T follicular helper cell clones during the germinal center reaction. We find that like germinal center B cells, T follicular helper cells undergo antigen dependent selection throughout the germinal center reaction resulting in differential proliferative expansion and contraction. Increasing the amount of antigen presented in the germinal center leads to increased T follicular helper cell division. Competition between T follicular helper cell clones is mediated by T cell receptor affinity for peptide-MHC ligand. T cells expanding preferentially in the germinal center show increased expression of genes downstream of the T cell receptor, genes required for metabolic reprogramming, cell division and cytokine production. These dynamic changes lead to dramatic remodeling of the functional T follicular helper cell repertoire during the germinal center reaction.