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dc.contributor.authorSymonds, Alistair
dc.date.accessioned2011-01-27T14:13:15Z
dc.date.available2011-01-27T14:13:15Z
dc.date.issued2009
dc.identifier.urihttps://qmro.qmul.ac.uk/xmlui/handle/123456789/409
dc.descriptionPhDen_US
dc.description.abstractTolerance of T cells to self-antigen is crucial to prevent the development of autoimmune disease. How self-tolerance is controlled at the transcriptional level is, however, unknown. We discovered that the transcription factor Early Growth Response 2 (Egr-2) was expressed by tolerant T cells, and by CD4+CD44high T cells in the absence of overt antigen stimulation, in vivo. To investigate the roles of Egr-2 in T cells, we generated CD2 cell specific Egr-2 deficient (Egr-2 cKO) mice. The proliferation of Egr-2 cKO CD44high T cells in vivo was markedly increased leading to progressive accumulation as the mice aged. By 15 months of age CD4+CD44high cells constituted the predominant T cell population in the peripheral lymphoid organs of Egr-2 cKO mice and expressed high levels of the activation markers CD25 and CD69. In addition to this lymphoproliferative disorder, 15 month old Egr-2 cKO mice showed signs of lupus-like autoimmune disease. This autoimmune syndrome was characterised by glomerulonephritis and proteinuria, infiltration of T cells into internal organs and, crucially, auto-antibodies directed against nuclear components; the hallmark of lupus. We observed decreased expression of the cyclin-dependent kinase inhibitor p21cip1 in Egr-2 cKO CD4+CD44high T cells while TCR stimulation induced IFN-γ, and, in particular, IL-17A and IL-17F expression was markedly increased. Consistent with these findings, we observed increased numbers of IFN-γ and IL-17 producing CD4+ T cells in Egr-2 cKO mice. The numbers of IFN-γ and IL-17 producing CD4+ T cells further increased as the mice aged in parallel with the gradual development of symptoms of lupus-like disease. These results demonstrate that Egr-2 is an intrinsic regulator of both T cell homeostasis and T cell tolerance.en_US
dc.language.isoenen_US
dc.subjectMedicineen_US
dc.titleThe zinc finger transcription factor Early Growth Response 2 (Egr-2) is an intrinsic regulator of T cell tolerance and homeostasisen_US
dc.typeThesisen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author


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    Theses Awarded by Queen Mary University of London

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