The homunculus in our thymus: a cellular genomics approach (360G-Wellcome-105045_B_14_Z)

Thymic epithelial cells (TEC) avert autoimmunity through their ability to promiscuously express virtually the entire protein-coding gene repertoire as a molecular library against which immature T cells are selected. An integrative analysis of the transcriptome, epigenome and proteome of distinct TEC subpopulations will be used to attain an unparalleled systems-level understanding of the molecular conditions that select a tolerant T cell repertoire under normal physiological conditions. Establish ing the molecular mirror of tissue specific self-antigen expression by single TEC has implications for understanding autoimmunity, the design of vaccines and the formation of a repertoire of tissue-specific regulatory T cells that can be co-opted by tumours to escape from immunological detection. Our findings will also be relevant for other areas of biology where stochasticity in gene expression of individual cells (e.g. stem cells) influences the establishment and maintenance of cell fate and function, and where gene silencing is overcome either as part of regular developmental programmes or in the context of malignant transformation. To achieve these aims we will develop generally useful new proteomic and microfluidic methods, single cell genomic and epigenetic technologies, novel mathematical models of cellular interaction, and new statistical approaches for understanding biology at single cell resolution.