Fig. 1

Simplified schematic of B cell routes to antibody secretion and humoral memory. Shown is a representation of progress along the B lineage along with limited highlights of metabolic regulators and changes in programming of intermediary metabolism in stages past the quiescent naive B cell stage (lower left) after antigen activation. The steps have been discussed in detail throughout this review, and more background on the signals and gene expression programs has been provided in earlier reviews [1,2,3, 56, 57]. For simplicity, issues unique to B1 and marginal zone B cells are omitted here. Successful BCR engagement and costimulation along with extrafollicular T cells help lead to increased cell mass and rounds of proliferative expansion that require large mTORC1-mediated increases in precursor uptake, macromolecule synthesis, energy generation, and maintenance of redox balance (middle left side). High-affinity BCR facilitates extrafollicular plasma cell generation (short- and long-lived plasma cells, i.e., SLPCs and LLPCs), with AMPK then restraining rates of protein synthesis (upper left), but memory B cells (MBCs) can also arise. Among the activated B cells, some with cognate help may move into the germinal center (GC) reaction that occurs in secondary follicles (middle of diagram). After a round of T cell help, proliferation, AID-induced mutations, i.e., somatic hypermutation (SHM), and p53-mediated apoptosis from genotoxic stress occur in the dark zone (DZ). Surviving progeny (~50%) move to the light zone (LZ), in which their BCRs can compete for capture of antigens from stromal cells (follicular dendritic cells (FDCs)), which can trigger apoptosis in the absence of help but allows internalization, epitope presentation on MHC-II, and enlistment of T cells. Apart from death and continuation in the GC, these B cells can assume a quiescent state that probably involves some degree of differentiation as MBCs (which can be subdivided according to IgM or CD80 and PDL2), some of which circulate to tissues. Alternatively, the cells can acquire a plasmablast/plasma cell fate in which IgG⁺ PCs supported by stromal niches can persist for months to years as LLPCs in the bone marrow. As discussed in the text, MBC persistence is promoted by both AMPK and canonical autophagy, whereas LLPC persistence appears to be autophagy-dependent but AMPK-independent