A continuum of CD4+ T cell “help” defines Memory B cell fate

Humoral immunity depends upon long-lived, antibody-secreting plasma cells and memory B cells (MBCs). MBCs exhibit significant phenotypic and functional heterogeneity. Upon homologous rechallenge, memory B cells thought to be of germinal center (GC) origin rapidly form antibody secreting plasmablasts but rarely enter a new GC, while other, less differentiated memory B cells enter secondary GCs, but do not form plasmablasts. These two populations therefore respond to a subsequent infection by generating antibody-secreting cells to epitopes not recognized by pre-existing serum and new populations of GC-derived MBCs that protect against novel variants. Understanding the mechanisms that regulate the differentiation of each unique population of MBCs during infection will help to define how to optimally drive the formation of these heterogeneous MBC cells via vaccination. We demonstrate a hierarchy of T-B interactions that leads to the generation of functionally distinct memory populations. One Sentence Summary A hierarchy of T-B interactions leads to the generation of functionally distinct memory B cell populations. ### Competing Interest Statement The authors have declared no competing interest.