Metabolic Regulation of the Immune Humoral Response

Abstract

Productive humoral responses require that naive B cells and their differentiated progeny move among distinct micro-environments. In this review, we discuss how studies are beginning to address the nature of these niches as well as the interplay between cellular signaling, metabolic programming, and adaptation to the locale. Recent work adds evidence to the expectation that B cells at distinct stages of development or functional subsets are influenced by the altered profiles of nutrients and metabolic by-products that distinguish these sites. Moreover, emerging findings reveal a cross-talk among the external milieu, signal transduction pathways, and transcription factors that direct B cell fate in the periphery.

Figure 1. The carbon economy – fuel and build

A schematic of the concepts and salient details outlined in the main text. (A) Both during quiescence and after activation and during growth, B cells need to balance the utilization of nutrients so as to generate ATP while also using portions of the uptake supply to provide building blocks for new molecule synthesis. As discussed in the text, the energy and atoms also get used for regulatory modifications such as histone post-translational modification by acetylation or methylation, or as cofactors of dioxygenases involved in HIF stabilization or the editing of chromatin methylation. Anabolic processes require both energy (ATP and GTP used in glycosylation as well as protein, lipid, and nucleic acid synthesis and the importation of sufficient building blocks. (B) Three major categories of fuel source are shown, along with some (but not all) of the branch points in their utilization. The plasma membrane is symbolized by an intermittent dotted line, in which nutrient importers are shown in simplified form (For instance, many can operate bi-directionally; some operate with export coupled to the import process shown). The mitochondrion is shown as a blue-bordered box, with only the Krebs cycle shown from among its many functions. Abbreviations: MCT, monocarboxylate transporter; LDH, lactate dehydrogenase; G6P, glucose-6-phosphate; ACLY, ATP-citrate lyase; PDH, pyruvate dehydrogenase; Ac-CoA, acetyl-Coenzyme A; αKG, alpha-ketoglutarate, also known as 2-oxoglutarate; TCA, tricarboxylic acid; GLS, glutaminase; ASCT2, Alanine, serine, cysteine-preferring transporter 2 (SLC1A5); LAT1, L-type amino acid transporter 1 (SLC7A5); NEAA, non-essential amino acids.

Figure 2. (A) A simplified view of cell surface receptors mediating B cell homeostasis and activation

For convenience, the PI 3-kinase activation is highlighted, as naïve & activated B cells are combined, along with helper T cells. Collaboration of BAFF-R, BCR and CD19, as noted in the text, are schematized. (B) A simplified diagram of signaling pathways linking surface receptors and metabolism in B cells. At the top level, multiple inputs into the phosphoinositide 3-kinase (PI3K) pathway from antigen (Ag) receptor, costimulators, and cytokine receptors are shown, along with PTEN conversion of phosphatidylinositol 4, 5-biphosphate (PIP2) to phosphatidylinositol 3, 4, 5-triphosphate (PIP3). The dual lipid-protein phosphatase PTEN (Phosphatase and tensin homolog) restrains the pathway. Antigen receptor signaling also includes activation of protein kinases C (PKC). PDK1, phospho-inositide-dependent kinase 1; TSC, tuberous sclerosis complex; GSK, glycogen synthase kinase; WNT, Wingless-related integration site; AMPK, AMP-activated kinase.

Figure 3. Transcriptional regulation of B cell metabolism

Schematic shows initial B cell activation by antigen and T cell help leading to the upregulation (green) and downregulation of key transcription factors. Events in the germinal center are dynamic as B cell traverse between selection in the hypoxic light zone (LZ) and proliferation in the dark zone (DZ). In the LZ, B cells retrieve antigen from follicular dendritic cell-bound antigen for presentation to TFH cells that reciprocate by providing cytokine support in the form of CD40L, IL-4 and IL-21. These cytokines induce the expression of select transcription factors that drive aspects of the metabolic program. The transcription factors c-Myc, HIF and STAT6 promote expression of glycolytic genes, whereas Bcl6 suppressed the transcription of some of the same target genes. HIF inhibits c-Myc activity which, among other events, would impair transcription of AP4 target genes.