Dokument: The role of SOCS3 in the regulation of T-cell activation and IL-7Rα expression
| Titel: | The role of SOCS3 in the regulation of T-cell activation and IL-7Rα expression | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=52820 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20200407-144653-9 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Güler, Mehmet Alptekin [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof.Dr. Jacobsen, Marc [Gutachter] Prof. Dr. rer. nat. Scheller, Jürgen [Gutachter] | |||||||
| Stichwörter: | SOCS3, T-cell activation, IL-7Rα | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Suppressor of cytokine signalling 3 (SOCS3) was initially described as a negative feedback inhibitor of cytokine signalling, but has also been associated with the regulation of T cell signalling and other pathways. Appropriate regulation of T-cell activation is crucial for both, pathogen clearance and for preventing excessive inflammatory responses. Interleukin-7 (IL-7) signalling is important for the homeostasis of naïve T helper cells and the development and maintenance of memory T helper cells, and mutations in the IL-7 signalling pathway result in severe immunological disorders. Impaired expression of the IL-7 receptor (IL-7R) has been associated with chronic infections and impaired development of memory T cells. IL-7R and SOCS3 are involved in the signalling of several mutual pathways and are dysregulated concomitantly in several diseases, among them tuberculosis. We showed previously elevated SOCS3 expression accompanied by decreased responsiveness against IL-7 in T cells of tuberculosis patients.
The aim of this study was to elucidate the role of SOCS3 during T-cell activation in primary human T helper cells. In activated T helper cells, SOCS3 expression increased two days after T-cell activation and accompanied the re-expression of IL-7Rα. SOCS3 expression was modulated with lentiviral constructs to overexpress or knockdown SOCS3 in activated primary human T cells. The specificity of constructs was verified in 293T HEK cell line by comparing it to the closely related protein SOCS1. Lentiviral transduction of T helper cells affected SOCS3 expression starting on day two after T-cell activation, without affecting the activation of resting T cells. Knockdown of SOCS3 (SOCS3kd) in T helper cells led to impaired re-expression of the IL-7Rα, and this was independent from signalling by IL-2 and IL-7. No differences in the expression or phosphorylation of Akt and FoxO1 were detected, both being regulators of IL-7Rα expression and downstream targets of SOCS3. In accordance, IL-7Rα mRNA levels were similar between SOCS3kd and control transduced T helper cells. Therefore, regulation of IL-7Rα by SOCS3 might be independent of the Akt/FoxO1 pathway and regulated on a post-transcriptional level. To address functional implications of differential IL-7Rα expression, T helper cells were co-transduced with SOCS3kd and control constructs thereby sharing the same culture conditions and competed for available growth factors and IL-7. IV SOCS3kd T helper cells showed lower proliferation rates, leading to lower proportions and absolute numbers in co-culture with control cells only in the presence of IL-7. This competitive disadvantage of SOCS3kd T cells could be attributed to decreased IL-7-induced signal transducer and activator of transcription 5 (STAT5) activation over the course of IL-7 signalling. Overall, these experiments provide evidence for a regulation of IL-7Rα expression during T-cell activation by SOCS3 and further implicate a role of SOCS3 in the development of memory T cells by promoting the re-expression of IL-7Rα after T-cell activation. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Sonstige Einrichtungen/Externe | |||||||
| Dokument erstellt am: | 07.04.2020 | |||||||
| Dateien geändert am: | 07.04.2020 | |||||||
| Promotionsantrag am: | 07.01.2020 | |||||||
| Datum der Promotion: | 11.03.2020 |
