Mapping the dynamics of memory B cell and plasma cell differentiation

Antigen-dependent B cell differentiation is an unusual developmental process, in which plasma cells (PCs) and memory B cells (MBCs) are generated by two distinct pathways – either directly from early activated B cells, or after induction of a specialized germinal center (GC) B cell program required for antibody affinity maturation.

Although such diversity of forms of immunological memory is of crucial importance as it can mediate protection against new variants of a pathogen, the field is largely focused on the events that take place in GCs, while the early waves of PCs and, in particular, MBCs are largely ignored.

Our results demonstrate that the pre-GC MBC fate is a ‘default’ lineage choice for activated B cells, a very large fraction of activated B cells early in the response takes this differentiation path and makes an unexpectedly large contribution to the long-lived MBC pool.

These results prompt in depth dissection of the molecular and functional properties of the pre-GC waves of MBCs and PCs and their comparison with the GC-derived cells.

In this project, we will combine cutting edge fate mapping, single cell transcriptomics and epigenomics approaches to perform a detailed molecular dissection of pre-GC and GC-derived MBCs and PCs. We will analyze how molecular properties of the two waves of MBCs program their functions.

Finally, we will use the knowledge obtained in mouse models to identify and analyze these cells in non-human primates and, ultimately, in humans.