Functional complementarity of mammalian coronins determines T cell population homeostasis

D'Otolo, Viviana. Functional complementarity of mammalian coronins determines T cell population homeostasis. 2022, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: https://edoc.unibas.ch/91059/

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To defend ourselves from invading pathogens, we are all equipped with an immune system, a complex network of cells and proteins. The skin already provides a first layer of defense against pathogens: however, when the microbes bypass this layer, they have to deal with immune cells. Key players of the immune response are T cells: originated in the bone marrow, T cells multiply and differentiate in the thymus before migrating into peripheral lymphoid organs or circulating within the blood, where they can recognize and eliminate foreign antigens. Therefore, it is crucial to maintain homeostatic numbers of T cells to guarantee a continuous response to pathogenic and tumor antigens.
The mammalian WD-repeat containing protein coronin 1, which is abundantly expressed in cells of hematopoietic origin including T cells and B cells, has been described to play a central function in T cell homeostasis. In fact, deletion or mutation of coronin 1 in mice and humans results in profound T cell deficiency, which particularly affects peripheral lymphoid organs such as the spleen and lymph nodes, despite apparently normal T cell selection and development in the thymus. Moreover, the naïve T cell pool is the one most impaired by the absence of coronin 1, while effector and memory T cells are less affected.
Coronin 1 is a member of a family of 7 mammalian proteins (coronin 1 to 7) that are evolutionarily conserved from yeast to humans and described to play a pivotal role in different cellular processes including transcription regulation, vesicular trafficking, remodeling of the cytoskeleton and signal transduction.
However, besides coronin 1, the role of the other coronins in T cells is poorly understood.
The purpose of this study was to assess whether other coronin family members, besides coronin 1, might play a role in T cell homeostasis.
Here we show that deletion of coronin 1 results in the upregulation of coronin 2 and coronin 3 in a human T cell line, suggesting that a compensatory mechanism is activated when a member of the coronin family is depleted. Furthermore, depletion of coronin 3 impaired T cell proliferation and survival, and the cells grew as aggregates in culture. These results suggest an important role for coronin 3 in cellular survival and raise the possibility that individual coronins cooperate to mediate T cell homeostasis. Moreover, coronin 3-depleted T cell lines show up-regulation of N-cadherin and non-phosphorylated-beta-catenin at the protein level, which might be responsible for the cell aggregation phenotype observed in the coronin 3-depleted cell lines.
Finally, the depletion of coronin 3 in coronin 1-deficient mice further enhances the T cell depletion phenotype that has been previously observed, confirming our hypothesis that the coronin family members might cover similar functions.
The results presented in this work suggest that multiple coronin family members cooperate, albeit via different mechanisms, to regulate T cell population homeostasis.
Advisors:Pieters, Jean and Affolter, Markus
Committee Members:Guarda, Greta
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Biochemistry (Pieters)
UniBasel Contributors:Pieters, Jean and Affolter, Markus
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14885
Thesis status:Complete
Number of Pages:115
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss148850
edoc DOI:
Last Modified:17 Dec 2022 05:30
Deposited On:16 Dec 2022 09:26

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