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Desert and Sonic Hedgehog Signalling in T cell Differentiation

Alshammary, AFJ; (2015) Desert and Sonic Hedgehog Signalling in T cell Differentiation. Doctoral thesis , UCL (University College London). Green open access

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T cells develop in the thymus. The thymus provides a unique microenvironment with all the cytokines, cell surface ligands and extra-cellular matrix components necessary for thymocytes to develop. The cellular programme of this development is well characterized, whereby CD4−CD8−double negative (DN) cells require preTCR induced signals to give rise to the CD4+CD8+ double positive (DP) cells. The DP population undergoes selection to form self-MHC restricted and selftolerant CD4+ or CD8+ single positive (SP) T cells. The Hedgehog (Hh) family of secreted intracellular signalling molecules plays a major role in many patterning processes and organogenesis during embryonic development and are involved in the homeostasis and renewal of adult tissues. This thesis focuses on studying the functions of hedgehog-pathway components in the thymus by detecting differences in T cell differentiation and transition from one developmental stage to the next. The Hh family member, Sonic Hedgehog (Shh) has been previously found to influence T cell development and transition at the double negative stage (DN). We have utilized T cell receptor transgenic mice models (TCR-transgenics) to investigate the role of Shh in T cell development and repertoire selection. Our data from thymic organ cultures (FTOCs) have shown that Shh influences T cell selection and maturation during the later stages of T cell development in their transition from DP to SP cell population. Another Hh family member, Dhh has been previously found to negatively regulate multiple stages of erythrocyte differentiation. Using Dhh-wild type and Dhh-knockout mice models, our data have shown that Dhh also play a negative regulatory role in T cell production in the thymus and peripheral lymphoid organs. Furthermore, we investigated the impact of Hh morphogene by utilizing Hh mutant mice and setting up different crosses to analyse transgenic repertoire selection in different mouse mutants, our data have shown that Hh-signalling regulate T cell development by attenuating gene transcription of various genes.

Type: Thesis (Doctoral)
Title: Desert and Sonic Hedgehog Signalling in T cell Differentiation
Event: UCL (University College London
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
URI: https://discovery.ucl.ac.uk/id/eprint/1470363
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