Modulation of T-cell apoptosis by small molecule compounds targeting the nuclear orphan receptor Nur77

Marquardsen, Florian. Modulation of T-cell apoptosis by small molecule compounds targeting the nuclear orphan receptor Nur77. 2018, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_12756

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Homeostasis within the adaptive immune system is a highly controlled process to avoid lymphoproliferation and immune-pathology. Controlled T- and B- cell death in the presence or absence of infection represents an important means to ensure adaptive immune cell homeostasis. Nur77, a nuclear orphan receptor of the NR4A subfamily, is rapidly induced following activation of T-cells and has been demonstrated to modulate apoptosis via diverse cellular mechanisms. Although no endogenous Nur77 ligand could be identified to date, pharmacological targeting of Nur77 with hydrophobic small molecule compounds such as the fungus-derived Cytosporone B and its derivate THPN (1-(3,4,5-trihydroxyphenyl)nonan-1-one) have been reported to induce apoptosis in various cancer types.
Here we report experimental evidence, that the Cytosporone B derivate TMPA (ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl) phenyl] acetate) in human and murine primary T-cell blasts dose-dependently impairs restimulation induced cell death (RICD) in a Nur77-independent manner. In addition, TMPA downregulates Nur77-dependently the intracellular adapter protein SAP by reducing mRNA expression of its gene SH2D1A. SAP is essential for immune control of EBV in humans and is critically involved in T-cell-dependent antibody- and auto-antibody formation.
To our knowledge, these data show for the first time, that T-cell intrinsic small molecule compound-mediated targeting of Nur77 induces a Nur77-independent antiapoptotic effect and a Nur77-dependent SAP downregulation. This evidence creates the basis to further investigate the therapeutic potential of targeting Nur77 with small molecule compounds, such as TMPA, in immune-control of tumors. Such compounds may induce Nur77-dependent apoptosis in cancer cells and at the same time reduce RICD of cancer-specific T-cells. Furthermore, Nur77-specific small molecule compounds may improve T-cell-dependent vaccinations (e.g. against HIV) or may limit in vivo apoptosis of adoptively transferred tumor-specific T-cells. The modulation of SAP expression by Nur77 binding small molecule compounds may be used to limit autoantibody formation in human autoimmune diseases.
Advisors:Recher, Mike and Khanna, Nina
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Immunodeficiency (Recher)
05 Faculty of Science
UniBasel Contributors:Recher, Mike and Khanna, Nina
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12756
Thesis status:Complete
Number of Pages:1 Online-Ressource (IV, 64 Seiten)
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edoc DOI:
Last Modified:16 Oct 2018 04:30
Deposited On:15 Oct 2018 13:04

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