Regulation of memory T cell lineage differentiation by epigenetic modifications

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DESCRIPTION (provided by applicant): Immunological memory is the basis for long-lasting protective immunity conferred by vaccination. The cells responsible for providing this protective immunity have different capabilities based on their location in the body, examples include sites exposed to the environment (i.e. lungs & intestine) or immune specific organs (i.e. lymph nodes). In order to construct better vaccines, we are trying to understand what drives the development of these different types of memory cells and how they might be related to one another. The memory T cell population is made up of at least two subsets of memory cells that have distinct homing and functional capacities. CD62L is important for the migration of lymphocytes through the high endothelial venules into lymphoid organs and is an effective marker in distinguishing 'central-memory' cells that reside in lymphoid organs and 'effector-memory' that reside largely in peripheral tissues. By having a diverse memory T cell population the host is provided with multiple layers of protection. How these subsets of memory cells are related to one another is an ongoing debate. We postulate that the two subsets are distinct cell lineages. In this proposal, we will examine whether epigenetic modifications occur within the memory precursor cells, which prevent the interconversion between these two subsets. We will examine whether during the immune response memory precursor cells that have lost CD62L expression have modified their chromatin in such a manner that precludes the re-expression of CD62L. We will also address how competition for resources/antigen affects this process. This proposal will allow us to gain a molecular understanding of memory cell differentiation through the use of chromatin immunoprecipitation assays, real-time RT-PCR and a CD62L reporter mouse system. By understanding how the responding CD8 T cells make their lineage decision we will be able to more effectively target a specific subset of memory cells which in turn may enable us to make more effective vaccines.