Petersone, Lina;
(2021)
Role of Interleukin 21 in Regulation of Germinal Centre Responses.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
While efficient germinal centre (GC) formation is the cornerstone of long-lasting humoral immunity against pathogens, dysregulated GC responses can lead to pathology. GCs are highly dynamic and complex microenvironments, and despite significant progress made during the past few decades, many questions about the key molecules involved in GC regulation remain unanswered. The work presented in this thesis investigated the role of the cytokine interleukin 21 (IL-21) in the regulation of GC responses. IL-21 has been shown to modulate GC responses in wildtype mice, and elevated IL-21 levels have been implicated in several autoimmune diseases, including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus. We have previously demonstrated that CTLA-4-/- mice develop spontaneous exacerbated GC responses as well as produce markedly elevated levels of IL-21. In this thesis, we used IL-21R-/-CTLA-4-/- animals to investigate the effects of IL-21 signalling in these chronic GCs and showed that IL-21 considerably increased the scale of CTLA-4-/- GC responses. More importantly, we also demonstrated that, in CTLA-4-/- mice, IL-21 significantly regulated GC B cell polarisation, and IL-21R deficiency led to a profound reduction in the GC dark zone compartment. Further analyses suggested that IL-21 supported the GC dark zone by promoting GC B cell selection and proliferation. Additionally, we demonstrated that our key findings in the CTLA-4-deficient model also applied to immunisation-induced transient GCs in wildtype animals. Furthermore, using wildtype and IL-21R-/- mixed bone marrow chimeric mice, we showed that dark zone GC B cell homeostasis was largely dependent on B cell-intrinsic IL-21 signalling. The findings presented in this thesis provide further insights into IL-21-dependent GC regulation. These will help advance our understanding of the generation of humoral immunity and may aid the development of novel and more targeted therapeutic strategies for patients suffering from a broad range of autoimmune conditions.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Role of Interleukin 21 in Regulation of Germinal Centre Responses |
| Event: | UCL (University College London) |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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 Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10118983 |
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