Damry, Djamil Ahmud;
(2021)
Role of TNFSF9 in germinal centre B cells and lymphoma formation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Members of the TNF superfamily play critical regulatory functions in hematopoietic cell lineage and function. Tnfsf9 is expressed in various hematopoietic cells, including B cells. Its receptor CD137, also known as 4-1BB, has been characterised and studied in the context of T cell activation and cancer immunotherapy. Loss of Tnfsf9 is recurrently found in human germinal centre (GC) B cell derived lymphomas and animals lacking Tnfsf9 develop B cell lymphomas. The use of genetically engineered mouse models may help to understand better the biology and function of Tnfsf9 in physiology and cancer. Here, we discover that animals completely deficient for Tnfsf9 display early in life enlarged lymph nodes and spleen, accompanied by spontaneous formation of large GCs. In addition, we investigate in a B cell specific manner the effects of Tnfsf9 loss and report a similar phenotype of spontaneous GCs. Protein microarray analysis of the sera of these mice shows the presence of both IgM and IgG autoantibodies, accompanied by immunoglobulin deposits in kidneys later in life. However, Tnfsf9 deficient animals do not show signs of overt autoimmune mediated pathology; they develop GC B-cell derived lymphomas with 100% penetrance as they age. We show that B cells deficient for Tnfsf9 display increased survival in vitro, and that this phenotype is accompanied by elevated Bcl-2 and Bcl-xL expression. Mechanistically loss of Tnfsf9 increases the activity of the alternative NF-kB signalling pathway upon BCR activation, by allowing increased nuclear translocation of p52. Our findings have implications for the understanding of B cell survival through the modulation of signals emanating from the BCR, and we report here a potential novel role of Tnfsf9 in linking BCR signalling and the alternative NF-kB pathway.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Role of TNFSF9 in germinal centre B cells and lymphoma formation |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10126695 |
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