Epigenomic landscape in naive, effector, and memory CD8 T cells

University Of Iowa, Iowa City IA

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Abstract

? DESCRIPTION (provided by applicant): CD8 T cells are critical in controlling infection by intracellular pathogens including viruses and intracellular bacteria. The ability to develop and sustain memory CD8 T cells after infection or immunization constitutes the basis for protective vaccination against infectious disease or in cancer immunotherapy. Since the level of protection against infection depends on the quality and quantity of memory CD8 T cells at the time of pathogen exposure, understanding the mechanisms that govern differentiation and maturation of the memory CD8 T cell pool are critical to our ability to design the most effective vaccines. CD8 T cell-mediated immune responses consist of several distinct stages, including activation of antigen-specific naïve CD8 T cells, clonal expansion of effector CD8 T cells, and formation of memory CD8 T cells. A plethora of protein factors including transcriptional regulators have been found to regulate each step of the CD8 T cell response, and high throughput transcriptomic analyses have revealed core gene signatures associated with naïve, effector and memory CD8 T cells. In spite of the tremendous progress, several knowledge gaps remains: 1) The heightened protective capacity by memory compared with naïve CD8 T cells cannot be solely explained by differences in transcriptomes. What are other molecular features that distinguish memory from naïve T cells? 2) Both effector and memory T cells are heterogeneous. What the lineage relationship among these subsets, and what are their defining molecular features? 3) Among the known regulatory factors, what are their target genes and how are they regulated, i.e., how their regulatory functions are coordinated during CD8 T cell responses? We hypothesize that the epigenetic modifications of CD8 T cell genome govern the effector-memory lineage relation and further confer enhanced recall response to memory T cells. Our specific aim is to map the dynamic changes of the epigenomes during CD8 T cell responses. We will isolate naïve T cells with pre- defined antigen specificity, and activate them using a well-established viral and bacterial infection model to obtain antigen-specific effector and memory T cells. By high throughput sequencing, we will map seven active and repressive histone marks in naïve, effector and memory CD8 T cell subsets. By integrative bioinformatics analyses, we will define: 1) Epigenetic code that distinguishes memory from naïve CD8 T cells; 2) Lineage relationship among subsets from effector and memory CD8 T cells; 3) Dynamic changes in enhancer organization and activity at each stage of CD8 T cell responses.