T cells dramatically change their metabolic output upon activation and response to infection, changing from quiescent naive T cells relying on oxidative phosphorylation (OXPHOS) to effector T cells engaging aerobic glycolysis before establishment and maintenance of memory requiring OXPHOS and lipolysis. However, what is unclear is the mechanism by which T cells acquire external metabolites, such as fatty acids, required for rapid clonal expansion, cell membrane biogenesis and production of effector molecules. Elucidation of how T cells import exogenous metabolites is essential for improving understanding of how diet, drugs and vaccines affect the T cell immune response. We have recently discovered that Major Facilitator Superfamily Domain Containing 2A (MFSD2A) is highly upregulated on activated murine T cells. MFSD2A is a protein expressed by endothelial cells at the blood brain barrier and is essential for the transport of omega-3 long-chain fatty acids, including docosahexaenoic acid (DHA), across the blood brain barrier. While the function of MFSD2A is known at the blood brain barrier, the role of this molecule and of imported long-chain fatty acid species in T cells are incompletely understood. We have extended our preliminary data to show that transport of long-chain fatty acids into activated T cells is dependent on MFSD2A expression. Moreover, we found that loss of MFSD2A expression on CD8+ T cells resulted in reduced response to infection and decreased production of effector cytokines. It is the central hypothesis of this proposal that MFSD2A is an essential protein for transport of external metabolites into activated T cells to support effector function. We propose the following aims: 1) Determine the role of MFSD2A in the CD8+ T cell immune response. Our preliminary data indicate an essential role for MFSD2A in robust CD8+ T cell response to infection leading to our hypothesis that MFSD2A expression is required to support T cell effector function. Using conditional MFSD2A-deficient mice, we will interrogate the role of MFSD2A in effector T cell activation, function, survival and differentiation. 2) Determine the physiological consequences of MFSD2A deficiency on the effector CD8+ T cell immune response. In this aim, we will delineate how MFSD2A expression affects the metabolism and gene expression of effector CD8+ T cells. Using our preliminary data as a basis for these studies and our conditional MFSD2A-deficient mice, we will perform (1) metabolic flux analysis to determine how loss of MFSD2A expression affects the metabolism of effector CD8+ T cells and (2) RNA-Seq analysis to assess differential gene expression in the presence and absence of MFSD2A on CD8+ effector T cells.

Public Health Relevance

The studies proposed herein will investigate the role of the lipid transporter MFSD2A on the effector T cell immune response. Given that the effect of diet and long-chain fatty acids on the T cell immune response has only recently been appreciated, the research proposed will elucidate how the lipid transporter MFSD2A can influence this process.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Ramachandra, Lakshmi
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University of Pittsburgh
Schools of Medicine
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