Abstract
A majority of B cell lymphomas originate from germinal center (GC) B cells. While somatic hypermutation in these cells can increase antibody affinity in response to infection, it can also cause collateral damage to DNA giving rise to cancer in this highly proliferative cell type. Successfully mutated antibody with increased affinity leads to increased antigen capture and presentation and subsequently increased follicular T cell help. T cell help in the light zone of the germinal center initiates a program of GC B cell proliferation with increased T cell help shortening the S phase and controlling dwell time in the dark zone where GC B cells proliferate. However, the mechanism underlying the number of cell cycles a selected B cell performs before returning to the light zone is elusive. We hypothesize that the number of cell cycles a selected GC B cell goes through is metabolically controlled by a mechanism in which a GC B cell is metabolically charged to perform a given number of divisions based on the strength of the selecting T cell signal. Once the metabolic charge is exhausted cells would return to the light zone for another round of selection. This metabolic charge could entail a) storage of metabolites, b) selection-controlled access to metabolites via temporal, e.g. transcriptional control of metabolite transporters or c) regulation of mitochondria function and metabolic enzymes of aerobic respiration. We are currently creating various mouse models to define the underlying mechanisms involved. To determine the contribution of metabolite transporters we will delete the main glucose transporter Glut1 in GC B cells using both constitutive deletion with AID-Cre and inducible deletion using AID-CreERT2. We are also constructing an IgHG1-IRES-CreERT2 mouse as an alternative to AID-CreERT2 and to potentially evaluate differences between IgM+ and IgG1+ cells. Using metabolic assays we will evaluate the status of glucose uptake, oxidative phosphorylation and mitochondrial function both by flow cytometric and microscopic methods. Using an established in vivo system in which we can selectively target a population of GC B cells for selection by loading them with antigen we will determine differences in metabolic states of selected and unselected GC B cells. Using an in vivo cell tracing assay in which mCherry fluorescent protein is diluted with cell division upon doxycycline treatment we will be able to determine differences in metabolic states of cells having highly proliferated or just having been selected. Our studies will show whether GC B cells are subject to the Warburg effect similar to malignant tumors and might in part explain the origin of the metabolic reprogramming seen in GC B cell-derived lymphomas. Understanding the underlying metabolic processes of GC B cells will not only help explain the emergence of B cell lymphoma but also their dependence on certain metabolic pathways. Specific factors important for metabolic regulation such as, but not limited to Glut1, will also be identified. These insights could eventually open up new avenues for B cell lymphoma treatment and particularly augment vaccination approaches both in tumor immunology and elsewhere.
Citation Format: Harald Hartweger, Shlomo Finkin, Michel C. Nussenzweig. Elucidating germinal center B cell metabolic states and their influence on selection [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B144.
RSS Feeds