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    The zinc finger transcription factor Early Growth Response 2 (Egr-2) is an intrinsic regulator of T cell tolerance and homeostasis 
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    • The zinc finger transcription factor Early Growth Response 2 (Egr-2) is an intrinsic regulator of T cell tolerance and homeostasis
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    • The zinc finger transcription factor Early Growth Response 2 (Egr-2) is an intrinsic regulator of T cell tolerance and homeostasis
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    The zinc finger transcription factor Early Growth Response 2 (Egr-2) is an intrinsic regulator of T cell tolerance and homeostasis

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    Abstract
    Tolerance 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.
    Authors
    Symonds, Alistair
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    https://qmro.qmul.ac.uk/xmlui/handle/123456789/409
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    • Theses [3705]
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    The 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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