Lymphocytes use considerable amounts of energy to maintain survival and to support growth and effector functions in response to antigen challenge. Aberrant glucose energy metabolism can contribute to autoimmune disease and lymphomas. During the past three decades the role of the B-cell antigen receptor (BCR) in promoting B-cell growth and development has been established. It is also clear that co-receptors (e.g., IgG Fc receptor, Fc?RIIB) can negatively modulate both Ag-dependent and Ag-independent growth responses. An appreciation for Fc?RIIB in the maintenance of peripheral tolerance is highlighted by the observation that its deletion can result in autoantibody production and autoimmune disease. BCR and Fc?RIIB mediated control of lymphocyte function likely requires re-programming of metabolism;however, virtually nothing is known about how signal input from these receptors modulate cellular metabolism or the biological significance of such regulation. On this point, we have recently discovered that the BCR possesses the capacity to reprogram glucose metabolism in real-time to meet the changing bioenergetic and de novo macromolecular synthetic demands associated with B lymphocyte activation. This is achieved by phosphatidylinositol 3-kinase (PI-3K)-dependent signaling that targets several essential rate-limiting enzymes involved in de novo lipogenesis (via activation of ATP citrate lyase, ACL), and entry into the oxidative pentose phosphate pathway (via induction of glucose 6-phosphate dehydrogenase (G6PD) gene expression) to support B-cell growth and DNA replication, respectively. We have also uncovered a novel pathway that links Fc?RIIB engagement to decreased glycolysis, a response remarkably similar to decreased glycolytic flux observed upon removal of growth factors from mammalian cells that leads to initiation of apoptosis. Our results suggest that the rate-limiting glycolytic enzyme, phosphofructokinase-1 (PFK-1) is inhibited following Fc?RIIB engagement. The central goal of this application is to delineate the molecular regulation of glucose energy metabolism involved in B lymphocyte function and growth responses by signal input from the BCR and Fc?RIIB. The proposed studies will seek to test two specific aims.
Aim I will elucidate the molecular regulation of ACL activation with respect to BCR-dependent signaling.
Aim II will elucidate the molecular mechanisms underlying inhibition of glycolysis following Fc?RIIB engagement. Information gathered from this project will also help to distill how dysregulation of glucose metabolism contributes to aberrant B-cell responses and may identify metabolic targets for the development of therapies to treat certain immune diseases characterized by uncontrolled expansion of B cells.

Public Health Relevance

Aberrant glucose energy metabolism can contribute to autoimmune disease and lymphomas. This proposal represents an opportunity to delineate the molecular mechanisms underlying how growth -promoting (B-cell antigen receptor) and -inhibitory (FcRIIB) signal input modulates glucose energy metabolism and to understand the biological significance of such regulation in B cells. Information gathered from this project will also help to distill how dysregulation of glucose metabolism contributes to aberrant B-cell responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074687-02
Application #
7843495
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2009-05-15
Project End
2011-12-30
Budget Start
2010-05-01
Budget End
2011-12-30
Support Year
2
Fiscal Year
2010
Total Cost
$391,250
Indirect Cost
Name
Boston College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
Xu, Chenjia; Wyman, Arlene R; Alaamery, Manal A et al. (2016) Anti-inflammatory effects of novel barbituric acid derivatives in T lymphocytes. Int Immunopharmacol 38:223-32
Dufort, Fay J; Gumina, Maria R; Ta, Nathan L et al. (2014) Glucose-dependent de novo lipogenesis in B lymphocytes: a requirement for atp-citrate lyase in lipopolysaccharide-induced differentiation. J Biol Chem 289:7011-24
Blair, Derek; Dufort, Fay J; Chiles, Thomas C (2012) Protein kinase Cýý is critical for the metabolic switch to glycolysis following B-cell antigen receptor engagement. Biochem J 448:165-9