Metabolic Regulation of CD8 T Cell Memory Development

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DESCRIPTION (provided by applicant): Immunological memory is the basis of vaccination, which may be the most significant public health tool available today. CD8 T cells play a crucial role in immunity to infections with intracellular pathogens. Upon stimulation, these T cells undergo a developmental program characterized by distinct phases encompassing first the expansion, and then contraction, of antigen-specific effector T cell populations, followed by the persistence of long-lived memory T cells that mediate immunity to re-infection. The mechanisms underlying the generation and maintenance of memory CD8 T cells remain unclear. Previously we demonstrated that mice lacking Traf6 (a TNFR and IL-1/TLR family adapter protein) in T cells mount effector CD8 T cell responses to infection, but are unable to establish memory CD8 T cells. Our experiments revealed that this CD8 T cell intrinsic failure of memory development was tightly linked to the inability of Traf6-deficient CD8 T cells to initiate mitochondrial fatty acid oxidation, a pathway of lipid catabolism that fuels the TCA cycle. Based on our observations, and a panel of supportive preliminary data, we hypothesize that catabolic processes of energy generation are essential for the development of memory CD8 T cells after infection and that Traf6 plays a key role regulating this process. We will test this hypothesis through the following specific aims: 1) Determine how fatty acid metabolism regulates memory CD8 T cell development; 2) Determine the extent of Traf6-dependent regulation of memory CD8 T cell development; and 3) Establish that pharmacological manipulation of CD8 T cell metabolism can be therapeutic. The long-term goal of these studies is to facilitate the development of immunotherapies against infectious diseases.