During infection the adaptive immune response has two primary goals, a short-term goal to eradicate the present infection and a long-term goal to establish immunological memory and protect against re- infection. These two goals are fulfilled by generating a heterogeneous pool of activated T and B cells that contain both short-term effector cells and memory cell precursors that persist long-term to seed a + pool of memory cells and provide exceptional protection agianst reinfection. Because cytotoxic CD8 T lymphocyte (CTL) responses are critical for clearing many types of intracellular infections and tumors, the development of many vaccines (e.g., HIV and plasmodium) are aimed at generating protective memory CD8 T cells. The question of how different types of memory T cells form during infection and vaccination and what genetic pathways and epigenetic changes control this process remains paramount. This past decade represents the dawn of a molecular understanding of memory CD8 T cell development, which largely through the use of well-characterized infection models in mice has discovered critical transcription factors and cytokine signaling pathways involved in this process. This work has delivered unprecedented insight into the genetic pathways that control memory T cell differentiation, but we are still in a discovery phase as only a handful of factors (cytokines and transcription factors (TFs)) have been identified that modulate effector and memory CD8 T cell differentiation in vivo during infection. Moreover, it is unclear how such factors cooperate or combat one another activities or to regulate the epigenetic states that specify effector and memory T cell fates. Elucidating these genetic and epigenetic networks is necessary to understand how the effector and memory T cell differentiation is controlled. It is likely that we will only really start to understand how T cell fates are specified and how the inherent heterogeneity and plasticity observed in T cells is controlled through studying the epigenome of T cells. Thus, the overarching goals of this MERIT extension are to elucidate genetic and epigenetic control of effector and memory CD8 T cell differentiation, plasticity and heterogeneity. This proposal will not only provide new insight on novel genetic regulators of effector and memory T cell development, but it will also reveal how effector T cell plasticity or commitment to terminal fates is regulated at the genomic level.
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