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dc.contributor.authorRobbins, Alissa Kathryn
dc.date.accessioned2021-08-20T02:15:26Z
dc.date.available2021-08-20T02:15:26Z
dc.date.issued2021
dc.identifier.urihttp://hdl.handle.net/11343/281335
dc.description© 2021 Alissa Kathryn Robbins
dc.description.abstractT cells are an essential component of the vertebrate adaptive immune system. In concert with the innate immune system, T cells protect the host from any number of pathogens that could be experienced over an organism’s lifetime. The hallmark of a T cell is its distinctive T cell receptor generated by somatic gene rearrangement. Variability in the T cell receptor repertoire arises during thymic T cell differentiation, which is then subjected to strict selection processes. Mature T cells in the periphery can undergo further differentiation upon the activation of naive cells to mount immune responses to pathogens. These differentiation events are accompanied by significant proliferative bursts, followed by the clearance of defective or superfluous cells. It follows then, that cell death is also an essential component of T cell differentiation and homeostasis. This PhD thesis explores the molecular mechanisms regulating the differentiation, proliferation and death of T cells, and how interplay among these mechanisms gives rise to immune homeostasis. This study examines how distinct cell death pathways, including the intrinsic and extrinsic apoptotic pathways and necroptosis, are differentially regulated through T cell differentiation and in the various subsets of mature T cells. We found that only inhibition of the intrinsic pathway of apoptosis overcomes failure of beta-selection in the absence of preTCR signalling or proliferation, enabling further differentiation. We also discovered that caspase 8 plays an important pro-survival role in inhibiting necroptosis in recent thymic emigrant T cells and regulatory T cells, and that this feature can be exploited in the case of regulatory T cells for therapeutic intervention in infection settings. In summary, this thesis defines context-specific roles of cell death modalities in controlling T cell differentiation and homeostasis, revealing the potential for immune interventions using targeted therapies.
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dc.subjectThymus
dc.subjectApoptosis
dc.subjectNecroptosis
dc.subjectCell death
dc.subjectRegulatory T cell
dc.subjectT cell differentiation
dc.titleCell Death Mechanisms in T cell Differentiation and Homeostasis
dc.typePhD thesis
melbourne.affiliation.departmentMedical Biology
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.thesis.supervisornameDaniel Gray
melbourne.contributor.authorRobbins, Alissa Kathryn
melbourne.thesis.supervisorothernameCharis En-Yi Teh
melbourne.thesis.supervisorothernameAndreas Strasser
melbourne.tes.fieldofresearch1310102 Cell development, proliferation and death
melbourne.tes.fieldofresearch2310111 Signal transduction
melbourne.tes.fieldofresearch3320404 Cellular immunology
melbourne.tes.fieldofresearch4321101 Cancer cell biology
melbourne.accessrightsOpen Access


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