Lymphocyte activation must be controlled to allow proper immunity while preventing inappropriate inflammatory immune responses. One element that we have found critical to support T cell growth, proliferation, and effector function is glucoe metabolism. In particular, the glucose transporter Glut1 and glycolysis are upregulated upon activation and differentiation of CD4 T cells into effectors (Teff; Th1, Th2, and Th17 are considered here). Regulatory T cells (Treg), however, express lower levels of Glut1 and utilize lipid oxidation rather than glycolysis as a primary metabolic program. Importantly, cell metabolism must match the demands of each cell type and we have shown that the inhibition of glucose metabolism prevents specification and function of Teff, while Treg are preferentially generated if glucose is limiting or glycolysis is inhibited. Manipulation of CD4 T cell metabolism,therefore, may provide a new approach to modulate immunity and reduce Teff function in inflammatory and autoimmune diseases. It is unclear, however, how T cell metabolism is regulated and what impact disruption of glucose metabolism may have in vivo, where a wide variety of alternate nutrients are available to potentially replace glucose. To address this question we have studied the role and regulation of Glut1 using a unique set of animal models. Our preliminary data show that Glut1 overexpression leads to selective lymphoproliferation of Teff while conditional deletion of Glut1 in T cells reduces peripheral T cell numbers and effector function. Regulatory mechanisms that control Glut1 may therefore provide potential targets for immune suppression. Indeed, we have recently shown that the orphan nuclear hormone receptor Estrogen Related Receptor-? (ERR?) plays a key role in the glucose metabolism and function of Teff and may mediate the effects of the Aryl- hydrocarbon Receptor (AhR) on CD4 specification into Teff or Treg via regulation of Glut1. We hypothesize that glucose uptake and metabolism are central regulators of effector T cell generation and function and that Glut1 regulation through AhR and ERR? may provide a novel avenue for therapy of immune diseases. We propose to: (1) Determine the role of Glut1 in T cell metabolism, survival, and effector function; (2) Establish regulatory pathways that control Glut1 expression and cell surface trafficking in murine and human T cell activation and in CD4 subsets; and (3) Examine the regulation and role of Glut1 in Teff generation and function in experimental autoimmune encephalomyelitis and graft-vs.-host disease. These studies will apply our unique set of animal models in normal activation and in two inflammatory diseases to directly establish the role of Glut1 and glucose metabolism in immune function and regulation of Glut1 and glucose metabolism as potential modulators of immunological disease.

Public Health Relevance

Inflammatory and autoimmune diseases affect millions of individuals and are often the consequence of inappropriate T cell activity. We have found that T cell glucose uptake and metabolism are highly regulated and can exert strong effects on T cell differentiation and function. This study will establish the role and regulation of the glucose transporter Glut1 in CD4 T cell metabolism and differentiation that may be exploited in novel metabolic approaches to modulate immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI102074-01
Application #
8513581
Study Section
Special Emphasis Panel (ZRG1-IMM-G (02))
Program Officer
Lapham, Cheryl K
Project Start
2012-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$392,500
Indirect Cost
$142,500
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Gerriets, Valerie A; Kishton, Rigel J; Nichols, Amanda G et al. (2015) Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest 125:194-207
Caro-Maldonado, Alfredo; Wang, Ruoning; Nichols, Amanda G et al. (2014) Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol 192:3626-36
Cao, Yilin; Rathmell, Jeffrey C; Macintyre, Andrew N (2014) Metabolic reprogramming towards aerobic glycolysis correlates with greater proliferative ability and resistance to metabolic inhibition in CD8 versus CD4 T cells. PLoS One 9:e104104
Macintyre, Andrew N; Gerriets, Valerie A; Nichols, Amanda G et al. (2014) The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20:61-72