Mengrelis, K;
(2016)
The role of Hedgehog signalling in the homeostasis and differentiation of GammaDelta and AlphaBeta T cells.
Doctoral thesis , UCL (University College London).
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Abstract
The Hedgehog (Hh) signalling pathway is an important mediator of many mammalian developmental processes and mutations in Hh genes cause serious developmental disorders and birth defects in both mice and humans. The role of Hh signalling in the development of αβTCR+ cells has been, and continues to be, explored by our and other laboratories. However, the impact of Hh signalling on unconventional T cells is not well characterised. Here, we aim to investigate the effect of Hh signalling on thymic and peripheral γδ T cells, both in mice and humans. Our study reveals that key components of the Hh pathway are present in the murine thymus and spleen and that γδ T cells are responsive to Hh signalling. Furthermore, flow cytometry of mutant mice revealed that Sonic (Shh) and Desert (Dhh) hedgehog affect γδ T cell biology in distinct ways. Our research detected numerous changes in cell numbers, key cytokine production, subtype differentiation, peripheral localization in both fetal and adult tissues and in a LPS-induced disease model. In humans, we expanded γδ thymocytes and assessed their responsiveness to Hh signalling. Furthermore, we investigated the role of Indian hedgehog (Ihh) in the transition from CD4-CD8- double negative (DN) to CD4+CD8+ double positive (DP) stage during αβ T cell development. Analysis of mice with conditional deletion of Indian hedgehog showed that Ihh negatively regulates DN to DP transition of αβTCR+ cells. Crossing of this conditional knockout (KO) to the male-specific antigen HY indicated that this effect is related to TCR rearrangement and signalling and thymic selection. Analysis of fetal and adult thymi also demonstrated that Ihh plays a role in DP to single positive (SP) transition too. Analysis of hydrocortisone (HC)-treated heterozygous Ihh and RagKO conditional Ihh mice further elucidated the role of Ihh in αβ T cell development.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | The role of Hedgehog signalling in the homeostasis and differentiation of GammaDelta and AlphaBeta T cells |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1498657 |
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