Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal

Abstract

A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38intBcl6hi/intEfnb1+ cells with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR that, in turn, contributed to their survival and development. We also found that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to adopt a memory B cell fate.

AMPK Metabolism in the B Lineage Modulates Humoral Responses

“…Immunization of mice harboring B cell-specific deletion of Prkaa1 with a T-dependent antigen revealed that AMPK initially dampens the generation of B cells harboring MBC surface markers when screening at a time coincident with the peak of the GC response in vivo [ 20 ]. On the surface, this finding differs from recent evidence that the GC B cell to MBC transition is facilitated by relatively lower mTORC1 activity in GC B cells [ 30 ]. In contrast to its role in dampening the initial population numbers of MBC, AMPK supports the long-term maintenance of the MBC population: numbers of Prkaa1 -deficient MBC were diminished compared to wild-type controls several weeks after the peak of the GC response [ 20 ].…”

“…As noted, AMPK is a negative regulator of mechanistic target of rapamycin complex 1 (mTORC1), a multi-subunit complex that promotes protein synthesis. mTORC1 and likely the dynamic regulation of its activity are critical for affecting outcomes of both germinal center and extra-follicular responses [ 27 – 30 ]. Loss of Prkaa1 in B cells led to elevated mTORC1 activity in vivo and after in vitro activation [ 20 , 31 ].…”

Naturally enhanced neutralizing breadth to SARS-CoV-2 after one year

“…The memory B cell compartment serves as an immune reservoir that contains a diverse collection of antibodies 13,14 . To enumerate RBD-specific memory B cells, we performed flow cytometry using a biotin-labeled RBD 3 (Fig.…”

Compartments and Connections Within the Germinal Center

“…In addition to driving affinity maturation, the GC selects for differentiation into both PCs and MBCs. Precursors of these populations must exist in the GC and, indeed, some have been identified ( 16 , 44 , 45 ). However, these populations are not observed upon simple division of the GC into two populations.…”

“…In contrast MBCs develop from low-affinity B cell clones that receive low strength signals from T FH ( 5 , 86 – 88 ). Weak T cell help also results in low Myc and mTORC1 activation, which also predisposes to differentiation into MBCs ( 44 ). Overall, these studies indicate that high affinity BCRs and strong T FH interactions predispose to PC differentiation while low affinity BCRs, and poor T cell help, leads to differentiation into MBCs.…”