Supplying the trip to antibody production-nutrients, signaling, and the programming of cellular metabolism in the mature B lineage

Abstract

The COVID pandemic has refreshed and expanded recognition of the vital role that sustained antibody (Ab) secretion plays in our immune defenses against microbes and of the importance of vaccines that elicit Ab protection against infection. With this backdrop, it is especially timely to review aspects of the molecular programming that govern how the cells that secrete Abs arise, persist, and meet the challenge of secreting vast amounts of these glycoproteins. Whereas plasmablasts and plasma cells (PCs) are the primary sources of secreted Abs, the process leading to the existence of these cell types starts with naive B lymphocytes that proliferate and differentiate toward several potential fates. At each step, cells reside in specific microenvironments in which they not only receive signals from cytokines and other cell surface receptors but also draw on the interstitium for nutrients. Nutrients in turn influence flux through intermediary metabolism and sensor enzymes that regulate gene transcription, translation, and metabolism. This review will focus on nutrient supply and how sensor mechanisms influence distinct cellular stages that lead to PCs and their adaptations as factories dedicated to Ab secretion. Salient findings of this group and others, sometimes exhibiting differences, will be summarized with regard to the journey to a distinctive metabolic program in PCs.

Keywords: B lymphocyte; Fatty acid; Glucose; Glutamine; Intermediary metabolism; Plasma cell; Signal transduction.

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 [–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

Fig. 2

Nutrient uptake and usage by pathways of intermediary metabolism linked to downstream processes. Simplified schema of items discussed in more detail in the body of the text. The extracellular milieux in which B lineage cells reside and through which they pass, in the upper portion of the diagram, may differ in concentrations of key constituents that include glucose, glutamine, essential amino acids (EAAs, i.e., those that cannot be synthesized in the B cells), and fatty acids (both short- and long-chain, i.e., SCFAs and LCFAs). The multiplicity of different transporters used for import (and in some cases export) of these nutrients is omitted from the picture, but as noted in the text, glucose may pass through at least three different molecules whose ratios may be different depending on the B lineage cell type, while glutamine has over four different routes. Several amino acids in addition to glutamine can be fed into mitochondria and the Krebs (TCA) cycle. The branch-point between glycolysis and the pentose phosphate shunt pathway at glucose-6-phosphate (G-6-P) is shown along with the mitochondrial pyruvate channel (MPC) as one route for pyruvate entry and conversion to acetyl-coenzyme A (Ac-CoA), but additional diversions of metabolites prior to ending glycolysis as pyruvate may be possible and are not shown. A suitably balanced combination of protein, nucleotide, and (phospho)lipid synthesis is required for clonal expansion, effector differentiation, and the execution of functions such as secretion of glycosylated antibody molecules, all of which also require energy (ATP)

Fig. 3

Summary of relationships and potential connections of BCR affinity, selected signals, and fate choices for B cells. As reviewed in the main text, the likelihood that a naive B cell, after its activation, flows into the memory pool, stably participates in a germinal center reaction, or undergoes extrafollicular differentiation directly to a plasma cell fate is influenced by BCR affinity (or avidity) for the antigen (indicated by the triangle and indicator arrow below it). GC B cells also contribute to the overall memory pool, generally after some degree of affinity maturation (not captured in this cartoon). Aspects of the relationship to signaling via ERK and mTORC1 activity are not fully established or settled, e.g., that high mTORC1 activity fosters increased PC differentiation among GC B cells. As discussed in the text, however, ERK^hi and mTORC1^hi cells appear to be favored for progression toward the PC fate, but whether BCR engagement by higher- versus lower-affinity ligands (antigens) causes heightened ERK or mTORC1 activity is not clear. For the memory pool, which will tend toward a more somatically mutated and selected BCR repertoire, memory cell activation will favor PC differentiation among BACH2^lo MBCs, but some activated memory cells do enter a new GC reaction, which in turn can yield new MBCs and ASCs