The importance of miR-17~92 during CD28 co-stimulation of murine CD4+ T cells

Dölz, Marianne. The importance of miR-17~92 during CD28 co-stimulation of murine CD4+ T cells. 2019, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: https://edoc.unibas.ch/71663/

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The prototypic costimulatory molecule CD28 is essential for proper CD4+ T cell activation and initiation of clonal expansion. CD28 ligation regulates metabolic adaptation, the production of cytokines, survival, differentiation but also T follicular helper cell generation and germinal center response. Moreover, CD28 signaling induces the expression of microRNA cluster miR-17~92 during CD4+ T cell activation. However, despite the importance of this receptor, the molecular understanding of how CD28 exerts its function remains incomplete.
In this thesis, we extend previous reports by showing that miR-17~92 expression directly correlates with CD4+ T cell activation, and miR-17~92-deficiency phenocopies CD28-deficiency in mice. We therefore hypothesized that transgenic miR-17~92 expression could substitute for the loss of CD28. Using a B6.CD4cre.R26floxstopfloxmiR1792tg.CD28ko mouse model, we demonstrate that transgenic miR-17~92 expression compensates for CD28 expression during CD4+ T cell activation and differentiation in vitro, but also in vivo during acute LCMV infection.
Even though many targets of miR-17~92 have been identified so far, the mechanisms by which miR-17~92 contributes to CD4+ T cell activation have not yet been fully explained. We generate transcriptomic datasets from activated CD4+ T cells with distinct amounts of miR-17~92 expression, with which we identify a new list of bona fide canonical miR-17~92 target genes. Furthermore, we demonstrate with a second dataset that these genes are not only regulated by miR-17~92 but also by CD28 expression. This shows that in addition to the activation of transcription during CD28 dependent CD4+ T cell activation, also the repression of genes which is mediated by miR-17~92 is essential. Moreover, the identified target genes mediate a rescue of the CD28ko transcriptome in rescue cells.
We furthermore identify a new miR-17 target regulator of calcineurin 3 (RCAN3) among the list of target genes. Our data strongly support a model in which miR-17~92, in addition to known pathways like PI3K, also regulates the NFAT pathway. This qualifies this miRNA cluster as an important regulator of CD28 co-stimulation, which could have broad implications for a better understanding of T cell activation and immunotherapy.
Advisors:De Libero, Gennaro and Hess, Christoph
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Tumorimmunologie > Tumorimmunologie (De Libero)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Tumorimmunologie > Tumorimmunologie (De Libero)
UniBasel Contributors:De Libero, Gennaro and Hess, Christoph
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14220
Thesis status:Complete
Number of Pages:131
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss142204
edoc DOI:
Last Modified:12 Aug 2021 09:11
Deposited On:12 Aug 2021 09:11

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