Metabolic regulation of epigenetic asymmetry in CD8 T lymphocytes

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CD8 T lymphocytes are able to undergo asymmetric cell division, which results in two daughter cell populations, differing in their metabolism as well as in their fate and function. Daughter cells that rise from the cell proximal to the immunological synapse show a more effector-like phenotype whereas daughter cells originating from the distal cell are more memory-like. Strikingly, the two cell populations also differ in their epigenetic signature. For example, the proximal daughter cell shows enhanced demethylation (an indication for active gene expression) of the Granzyme B promoter, a key player in effector T lymphocytes, which is in line with the effector-like phenotype of this cell population during influenza virus infection. This raises the intriguing possibility that the fate of a T lymphocyte is preset prior to its first division by protein and nutrient gradients, transmitted through metabolites, to be finally imprinted into the epigenome. Therefore, the proposed project aims to investigate the hypothesis that i) the asymmetric epigenetic signature of first division CD8 T lymphocytes is established and maintained metabolically and ii) that the fate of these cells can be modified by manipulating the epigenetic imprint. We propose that asymmetric arrangement of amino acid transporters as an early event following T cell activation results in an amino acid gradient and polarized TORC1 activity. As the T cell undergoes its first division, asymmetric availability of metabolites might result in differential levels of activity of epigenetic enzymes, which might account for the observed asymmetric demethylation in first division T cells. Also, a differential level of c-Myc in the two daughters might contribute to availability of metabolites by affecting the expression level of metabolic enzymes or may act to increase the expression of epigenetic enzymes directly. Further, the proposed project aims to investigate the role of DNA methylation in the maintenance of asymmetry by regulating the expression of amino acid transporters, TORC1 signaling components, or c-Myc. Finally, we will test the idea that differential epigenetic signatures and cell fate can be manipulated by targeting metabolic processes.