Webb, LV;
(2016)
The role of NF-κB signalling in T cell homeostasis and function.
Doctoral thesis , UCL (University College London).
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Abstract
Inhibitor of NF-κB kinase 1 (IKK1) and 2 (IKK2) form part of the functional IKK complex, necessary for NF-κB signalling. NF-κB is vital for survival, development, and function of multiple cell types. The aim of this study was to determine the function of NF-κB in thymic development and maintenance of the peripheral T cell compartment. For this, we used the Cre-loxP system in order to delete one or both of the Ikk1 and Ikk2 genes in T cells. Developmental deletion of Ikk1 and Ikk2 in CD4 CD8 double negative thymocytes revealed that NF-κB signalling was, surprisingly, redundant for early stages of thymic development and selection. Instead, late stage maturation of single positive thymocytes was abruptly halted in the absence of Ikk1 and Ikk2. Double deficient mice had a severe reduction in mature HSA low single positive thymocyte numbers and scarcely any peripheral T cells. Members of the TNF receptor superfamily (TNFRSF) are potent activators of NF-κB. We therefore tested the hypothesis that TNFRSF signalling could be regulating developing thymocytes. In vivo blockade of TNF in the IKK1/2 double deficient animals resulted in an almost complete rescue of thymocyte development. Cell culture experiments revealed that IKK1/2 double deficient thymocytes were specifically susceptible to TNF induced death. TNF receptor 1 (TNFR1) was identified as the key surface receptor, and TNFR1 IKK1/2 triple deficient mice had normal thymic development. Although TNFR1 is expressed throughout thymic development, transcriptomic analysis revealed cIAP2 and IL-7Rα as key targets of NF-κB dependent TNF signalling, but that co-operative developmental regulation of RIPK1 and caspase-8 underpinned the developmental susceptibility of mature SP thymocytes to TNF induced apoptosis. Our data reveal that developmental tuning of TNFR signalling and response genes is critical for normal T cell development and homeostasis.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | The role of NF-κB signalling in T cell homeostasis and function |
| Event: | University College London (UCL) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Keywords: | NF-κB, IKK, T cells, Thymocytes, TNF, IL-7R, RIPK1, Thymic development, TNFR1, Flow cytometry, IKK1, IKK2 |
| 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/1485803 |
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