Sahni, H; (2014) The molecular regulation of T cell development and function (Sahni, , Trans.). Doctoral thesis , UCL (University College London).

Abstract

The thymus provides a unique microenvironment with all cytokines, cell surface ligands and extra-cellular matrix components necessary T cells to develop. The cellular programme of this development is well characterized, whereby CD4-CD8-double negative (DN) cells require pre-TCR induced signals to give rise to the C04+CD8+ double positive (DP) cells. The OP population undergoes selection to form self-MHC restricted and self-tolerant C04 or CD8 single positive T cells. Extensive work has helped to identify few genes that are important in the pre-TCR induced ON to DP transition. However, our understanding of the temporal regUlation of the genome-wide molecular events underpinning the developmental programme remains restricted. The work done in this thesis focusses on addressing this gap in the understanding of T cell development. Using time course microarrays on thymocytes sorted from foetal thymic organ cultures (FTOCs), transcriptomes of developing T cells were measured through time during the ON to OP transition. A transcriptional modelling strategy, based on the principle that gene expression observed at a particular moment is the balance of synthesis and degradation of its mRNA, was applied. This allowed dissection of the transcriptional signature of the pre-TCR by temporally integrating all the molecular mediators under the pre-TCR signal into defined transcriptional groups. The study revealed previously unknown regulatory factors regulating this phase of T cell development, a few of which, such as the transcriptional repressor Bcl6, were tested in vitro. I describe here, a role for Bcl6 in promoting preTCR induced ON to OP differentiation, and I identify the genes repressed by it, in developing thymocytes. Among them, were members of the Fragilis protein family that are also targets of morphogens including Hedgehog (Hh) proteins, which regulate T cell development in the thymus and differentiation in the periphery. Fragilis proteins were found to influence multiple stages of thymocyte development and function. Genome wide analysis revealed a possible mechanism upstream of Stat1 and the IL27 receptor. Finally, the molecular mediators regulated by Hh signalling at the ON to OP stage are examined, using time course microarrays on foetal thymocytes from a transgenic Gli2 mouse model. This identified a group of transcriptional targets including Bmp4, which can signal directly to thymocytes and attenuate the pre-TCR induced ON to OP differentiation.

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