Cellular immunity is essential for durable resistance to viruses and other intracellular pathogens. Because the system is based on the level of the cell, survival or death of individual T cells is a key decision for proper immune function. A bevy of in vitro studies have suggested that metabolic fitness is a key factor in T cell survival decisions, yet few studies have addressed this question in vivo in the context of homeostasis or response to infection. Furthermore, genetically induced overactive metabolic flux may indeed bypass the T cell requirement for co-stimulation, a key safety mechanism preventing improper immune function such as autoimmunity. In preliminary experiments, we find that deletion of pVHL in activated T cells results in increased glycolytic flux in T cells and promotes their survival. We propose using this genetic tool to investigate the role of metabolic fitness in T cell survival in normal homeostasis and response to infection. It is anticipated that the results of this research will shed light on where metabolic fitness lies in the hierarchy of complex inputs that ultimately result in T cell survival or death, a delicate balance that if perturbed can result in either autoimmunity or vulnerability to infection. Because aberrant T cell survival may play a role in the failure to tolerate self that is the hallmark of such autoimmune diseases such as lupus and psoriasis, this research has special clinical relevance in addition to its underpinnings in basic immunology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI082933-02
Application #
7941831
Study Section
Special Emphasis Panel (ZRG1-F07-E (20))
Program Officer
Prograis, Lawrence J
Project Start
2009-07-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$50,474
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Delpoux, Arnaud; Lai, Chen-Yen; Hedrick, Stephen M et al. (2017) FOXO1 opposition of CD8+ T cell effector programming confers early memory properties and phenotypic diversity. Proc Natl Acad Sci U S A 114:E8865-E8874
Doedens, Andrew L; Rubinstein, Mark P; Gross, Emilie T et al. (2016) Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance. Cancer Immunol Res 4:799-811