Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.617010
Title: The transcriptional regulation of T-cell differentiation
Author: Roychoudhuri, Ranul
ISNI:       0000 0004 5348 3763
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2014
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Abstract:
Through their functional diversification, T cells not only provide protection from a multitude of infectious agents but can act to both drive and constrain immune-mediated pathology. A locus encoding the transcription factor BACH2 is associated with diverse immune-mediated diseases including asthma, celiac disease, Crohn's disease, mUltiple sclerosis, generalized vitiligo and type 1 diabetes in humans. Despite this, a function for Bach2 in the maintenance of immune homeostasis had not been defined. We found that genetic ablation of Bach2 in mice resulted in the development of spontaneous lethal inflammation predominantly affecting the lungs and gut. Analysis of both thymic and induced Treg cell development revealed a cell intrinsic requirement for Bach2 in the formation of Treg cells. As a result, using bone marrow reconstitution experiments, we found that Bach2 was required for prevention of lethal inflammation in a manner that was FoxP3 and Treg cell dependent. In addition to CD4+ Treg cells, however, Bach2 was highly expressed in naive cells and lost upon effector differentiation. Strikingly, overexpression of Bach2 prevented differentiation into effector cells, suppressed cytokine production and resulted acquisition of memory-cell characteristics. Conversely, while naive Bach2- deficient CD8+ T cells formed effector responses following viral infection in vivo, there was a near-complete cell-autonomous defect in their ability to generate long-lived memory cells. Accordingly, deficiency of Bach2 resulted in impaired protective immunity following primary responses and Bach2-deficient cells exhibited impaired long-term anti-tumor functionality.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.617010  DOI: Not available
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