A dynamic T cell–limited checkpoint regulates affinity-dependent B cell entry into the germinal center

TLDR

The germinal center reaction generates high‑affinity, somatically hypermutated antibodies, yet only a few B‑cell clones enter the GC and the mechanism selecting these clones remains unclear. The study shows that low‑affinity B cells cannot expand or activate when higher‑affinity B cells are present before germinal center formation, and proposes that T‑cell help is limited to B cells presenting the most pMHC, creating a dynamic affinity threshold. The authors model T‑cell help as being selectively delivered to B cells displaying the greatest pMHC density, establishing a dynamic affinity threshold. Live multiphoton imaging revealed that selection of B cells depends on the quantity of pMHC presented to T cells at the T–B border, causing low‑affinity B cells to fail to expand in the presence of higher‑affinity B cells.

Abstract

The germinal center (GC) reaction is essential for the generation of the somatically hypermutated, high-affinity antibodies that mediate adaptive immunity. Entry into the GC is limited to a small number of B cell clones; however, the process by which this limited number of clones is selected is unclear. In this study, we demonstrate that low-affinity B cells intrinsically capable of seeding a GC reaction fail to expand and become activated in the presence of higher-affinity B cells even before GC coalescence. Live multiphoton imaging shows that selection is based on the amount of peptide–major histocompatibility complex (pMHC) presented to cognate T cells within clusters of responding B and T cells at the T–B border. We propose a model in which T cell help is restricted to the B cells with the highest amounts of pMHC, thus allowing for a dynamic affinity threshold to be imposed on antigen-binding B cells.