Early Memory B Cells in Humans are Primed for Plasma Cell Differentiation and are Refractory to Reactivation

In this study, we report that CD19+CD27+CD21lo (CD21lo) B cells are transiently enriched for antigen specificity 14-28 days post-immunization, at the time germinal centers (GCs) peak. While clonally related to memory B cells and plasmablasts, CD21lo cells form distinct clades within phylogenetic trees based on accumulated variable gene mutations, supporting exit from active GCs. CD21lo cells express the Blimp-1 transcriptional program suggesting they are primed for plasma cell differentiation and refractory from GC differentiation, though they do not secrete antibody. Further, they down-regulate tissue and GC homing molecules, they are inhibited from re-activation, and appear more susceptible to negative selection. Together, this data supports a model in which CD21lo cells are recent GC graduates that are refractory to GC reentry, preventing disruption of the affinity maturation process of lower affinity B cells. Further, we propose these cells represent the stage when selection against mutation-induced reactivity to body-wide autoantigens occurs.