Metabolism is reemerging as a major factor that regulates the function of immune cells and influences the course of an immune response. Studying how metabolic changes in immune cells can have an effect on the immune response is becoming a major area of interest in immunology. Due to their exponential expansion in response to antigen stimulation, the effect of metabolism in T cells is more prominent. However, in addition to proliferation changes in metabolism can also affect effector function (e.g. cytokine secretion, cytotoxicity). As a result, control of T cell metabolism is emerging as an alternative strategy to modulate the immune response, either to increase (e.g. vaccination and infectious disease) or decrease (e.g. chronic inflammatory diseases, transplant rejection) the strength of the immune response. Novel approaches to modulate the metabolism of T cells will be therefore highly beneficial. A number of studies have shown that both CD4 and CD8 T cells undergo a reprograming of their metabolic pathways and the nature of "nutrients" that lead to the generation of ATP as the main source of metabolic energy. Na?ve cells use glucose and free fatty acids (FFA) as source of ATP through mitochondrial oxidative phosphorylation (OXPHOS). During activation, CD8 T cells switch to a glycolytic pathway in the cytosol. Effector T cells also use glutamine as another source of generating ATP in mitochondria through the OXPHOS. During the transition from effector to memory cells, metabolic pathways again undergoing a reprogramming and memory CD8 T cells prefer fatty acid oxidation through OXPHOS in mitochondria as a source of ATP. Interestingly, pathogenic T cells in inflammatory diseases and alloreactive T cells in GVHD also use primarily OXPHOS as source to obtain ATP. Thus, mitochondria are a central common engine to generate ATP (with the exception of glycolysis) in T cells independently of the status of activation. Little is known about endogenous mechanisms that control mitochondria respiration and, thereby, the immune response. We have recently identified MCJ/DnaJC15 as an endogenous inhibitor of the electron transfer chain (ETC). MCJ is abundantly expressed in CD8 T cells, with little expression in CD4 T cells or other immune cells. We have shown that MCJ is a highly conserved protein in vertebrates and localizes in the inner membrane of the mitochondria where it can interact with Complex I to attenuate its activity and restrict mitochondrial metabolism. Loss of MCJ results in a rapid metabolism of lipids in the liver. We propose that in CD8 T cells the function of MCJ is to provide a negative feedback over mitochondrial OXPHOS and ATP synthesis by mitochondria to attenuate their metabolism and maintain these cells at a more quiescent stage. We propose: 1) To identify the role of MCJ in the generation and function of effector and rested effector CD8 T cells (Aim 1);and 2) To investigate whether MCJ regulates the generation and/or function of memory CD8 T cells and protection against influenza viral infection (Aim 2). MCJ could be emerging as a potential target to modulate CD8 T cell metabolism.

Public Health Relevance

Metabolism is reemerging as a major factor that regulates the function of immune cells and influences the course of an immune response. Studying how metabolic changes in immune cells can have an effect on the immune response is becoming a major area of interest in immunology. Due to their exponential expansion in response to antigen stimulation, the effect of metabolism in T cells is more prominent. However, in addition to proliferation changes in metabolism can also affect effector function (e.g. cytokine secretion, cytotoxicity). As a result, control of T cell metabolism is emerging as an alternative strategy to modulate the immune response: 1) to increase the strength of immune response to vaccination and infectious disease, 2) or decrease immune response to ameliorate chronic inflammatory diseases (e.g. arthritis, lupus, asthma etc) or reduce the risk of transplant rejection. Novel approaches to modulate the metabolism of T cells will be therefore highly beneficial. We have recently identified MCJ (Methylation-Controlled J protein) (also called DnaJC15) as an endogenous inhibitor of mitochondrial metabolism and shown that loss of MCJ results in an accelerated metabolism and reduction of lipid accumulation in liver (including reduced cholesterol). We have also discovered that MCJ is abundantly expressed in CD8 T cells and loss of MCJ results in a sustained mitochondrial metabolism. We propose to investigate the role of MCJ in CD8 T cell mediated immune response. We will also examine whether in the absence of MCJ the immune response to influenza virus vaccines is superior. The results from these studies will reveal whether MCJ could be used as a potential target to modulate CD8 cell metabolism and immune response. In addition, since MCJ expression can be lost due to gene modifications, it is possible that presence of MCJ could be a factor contributing to the disparity in response to vaccines or the risk to develop autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI110016-01A1
Application #
8726663
Study Section
Special Emphasis Panel (ZRG1-IMM-K (02))
Program Officer
Mallia, Conrad M
Project Start
2014-02-10
Project End
2016-01-31
Budget Start
2014-02-10
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$205,875
Indirect Cost
$70,875
Name
University of Vermont & St Agric College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405