Single-cell analysis of the molecular regulation of T cell differentiation

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Cell differentiation, i.e. the process of a cell becoming different cells with specialized functions, is fundamental to biology. Essential to a healthy immune system is the diversity in T cell fate and function. Much of our understanding of how T cells differentiate is based on studies on groups of T cells that have different functions. However, to better understand how different T cell fates and functions are formed requires analyzing single cells during differentiation. Advances in single-cell genomics technologies have begun to enable the direct molecular analysis of single cells and their differentiation lineages, revealing drivers of cell fate decisions and molecular heterogeneity at the single cell level. *** To induce T cell activation and differentiation, immune antigen presenting cells recognize foreign agents and present them to receptors on T cells (called cognate-peptide interactions). Together with transcriptional networks, epigenetic regulation of gene transcription and asymmetric division can contribute to specifying different T cell fates early after T cell activation by cognate-peptide interactions. In previous works, using single-cell gene expression analyses, we provided novel transcriptional and epigenetic insights into how single mouse T cells diverge into different paths of differentiation early after T cell activation. *** The long-term aim of this research is to characterize the molecular mechanisms that regulate cell fate decisions and cell differentiation processes at the single-cell level. The short-term aims are to characterize the early transcription and chromatin accessibility patterns in single T cells undergoing differentiation after activation by different cognate-peptide interactions. A multidisciplinary approach, including single-cell transcriptomics and epigenomics, cell biology, immunology models of T cell differentiation, and computational analyses, will be used to characterize early molecular mechanisms underlying T cell differentiation. The research proposed over this 5 year cycle will provide training opportunities in single cell genomics and immunology research for at least four graduate students (two Master of Science and two Doctor of Philosophy trainees) and four undergraduate students, and will form the basis for future research projects on cell differentiation and ongoing research training opportunities. *** This research is significant to address a gap in cell differentiation: cell-to-cell heterogeneity in chromatin accessibility regions, which would reflect the differentiation of epigenetic states among single cells at early phases of cell fate specification, remains unknown. This research will provide novel insights into the fundamental molecular mechanisms regulating gene expression and cell fate specification during cell differentiation and T cell biology. The findings from this research will be broadly applicable to the study of how other cellular systems of differentiation are regulated. **