Regulation of T cells in Atherosclerosis
(2023) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Atherosclerosis, the underlying pathology of cardiovascular diseases such as myocardial infarction and ischemic stroke, is characterized by chronic inflammation. T cells are present in atherosclerotic plaques and have been implicated in its pathogenesis. This thesis describes studies exploring both the regulation of T cells in atherosclerosis as well as immunomodulatory therapeutics.
To study the role of IL-2 signaling, we selectively delivered IL-2 to T effector memory cells via administration of IL-2 complexed to the anti-IL-2 clone S4B6 (IL-2/S4B6) in atherosclerotic mice. IL-2/S4B6 administration resulted in increased levels of effector memory T cells and NK cells and their capacity to produce IFN-γ, increased... (More) - Atherosclerosis, the underlying pathology of cardiovascular diseases such as myocardial infarction and ischemic stroke, is characterized by chronic inflammation. T cells are present in atherosclerotic plaques and have been implicated in its pathogenesis. This thesis describes studies exploring both the regulation of T cells in atherosclerosis as well as immunomodulatory therapeutics.
To study the role of IL-2 signaling, we selectively delivered IL-2 to T effector memory cells via administration of IL-2 complexed to the anti-IL-2 clone S4B6 (IL-2/S4B6) in atherosclerotic mice. IL-2/S4B6 administration resulted in increased levels of effector memory T cells and NK cells and their capacity to produce IFN-γ, increased pro-inflammatory cytokines in plasma, and increased regulatory T cells, but no effects on subvalvular plaque size or composition. Additionally, IL-2/S4B6 treatment decreased total plasma cholesterol and lipid-lowering effects were contingent on the presence of adaptive immune cells.
We next set out to characterize interferon-γ (IFN-γ)-producing aortic T cells. Utilizing an atherosclerotic IFN-γ-reporter mouse model, we identified that IFN-γ+ T cells in the atherosclerotic aorta are characterized by elevated PD-1 expression. These cells are not functionally exhausted and respond to anti-PD-1 antibody treatment by increased IFN-γ production, possibly providing a mechanism behind the increased cardiovascular risk in patients after receiving anti-PD-1 therapies. Furthermore, we show that administering anti-LAG-3 therapies in combination with anti-PD-1 exacerbates T cell infiltration into the plaque.
Lastly, we tested a novel monoclonal antibody blocking the IL-1 receptor accessory protein (IL1RAP) in atherosclerotic mice. Administration of anti-IL1RAP antibodies, which disrupt the signaling of IL-1α/β, IL-33, and IL-36α/β/γ concomitantly, resulted in decreased plaque burden and reduced immune cell infiltration into both the atherosclerotic plaque and surrounding adventitia. We propose these results were in part mediated by reduction of gene expression for the adhesion molecules ICAM-1 and VCAM-1 as well as reduced CXCL1 chemokine production by macrophages and fibroblasts.
Our results support further studies into anti-IL1RAP as a therapeutic for atherosclerosis. Furthermore, we provide mechanistic insight into how immune checkpoint inhibitor therapy increases cardiovascular risk, by “releasing the brake” off IFN-γ+ T cells in the plaque, potentially leading to increased plaque vulnerability and adverse events. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/ae9ef547-147a-478f-8c90-a6447a7eb5cf
- author
- Mulholland, Megan LU
- supervisor
- opponent
-
- MD, PhD Caligiuri, Giuseppina, Université Paris Cité and Université Sorbonne Paris Nord, INSERM, Laboratory for Vascular Translational Science (LVTS), Paris, France
- organization
- publishing date
- 2023
- type
- Thesis
- publication status
- published
- subject
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2023:150
- pages
- 117 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Agardh föreläsningssal, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö
- defense date
- 2023-12-08 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-492-6
- language
- English
- LU publication?
- yes
- id
- ae9ef547-147a-478f-8c90-a6447a7eb5cf
- date added to LUP
- 2023-10-27 15:57:32
- date last changed
- 2023-11-17 10:23:54
@phdthesis{ae9ef547-147a-478f-8c90-a6447a7eb5cf,
abstract = {{Atherosclerosis, the underlying pathology of cardiovascular diseases such as myocardial infarction and ischemic stroke, is characterized by chronic inflammation. T cells are present in atherosclerotic plaques and have been implicated in its pathogenesis. This thesis describes studies exploring both the regulation of T cells in atherosclerosis as well as immunomodulatory therapeutics. <br/><br/>To study the role of IL-2 signaling, we selectively delivered IL-2 to T effector memory cells via administration of IL-2 complexed to the anti-IL-2 clone S4B6 (IL-2/S4B6) in atherosclerotic mice. IL-2/S4B6 administration resulted in increased levels of effector memory T cells and NK cells and their capacity to produce IFN-γ, increased pro-inflammatory cytokines in plasma, and increased regulatory T cells, but no effects on subvalvular plaque size or composition. Additionally, IL-2/S4B6 treatment decreased total plasma cholesterol and lipid-lowering effects were contingent on the presence of adaptive immune cells. <br/><br/>We next set out to characterize interferon-γ (IFN-γ)-producing aortic T cells. Utilizing an atherosclerotic IFN-γ-reporter mouse model, we identified that IFN-γ+ T cells in the atherosclerotic aorta are characterized by elevated PD-1 expression. These cells are not functionally exhausted and respond to anti-PD-1 antibody treatment by increased IFN-γ production, possibly providing a mechanism behind the increased cardiovascular risk in patients after receiving anti-PD-1 therapies. Furthermore, we show that administering anti-LAG-3 therapies in combination with anti-PD-1 exacerbates T cell infiltration into the plaque.<br/><br/>Lastly, we tested a novel monoclonal antibody blocking the IL-1 receptor accessory protein (IL1RAP) in atherosclerotic mice. Administration of anti-IL1RAP antibodies, which disrupt the signaling of IL-1α/β, IL-33, and IL-36α/β/γ concomitantly, resulted in decreased plaque burden and reduced immune cell infiltration into both the atherosclerotic plaque and surrounding adventitia. We propose these results were in part mediated by reduction of gene expression for the adhesion molecules ICAM-1 and VCAM-1 as well as reduced CXCL1 chemokine production by macrophages and fibroblasts. <br/><br/>Our results support further studies into anti-IL1RAP as a therapeutic for atherosclerosis. Furthermore, we provide mechanistic insight into how immune checkpoint inhibitor therapy increases cardiovascular risk, by “releasing the brake” off IFN-γ+ T cells in the plaque, potentially leading to increased plaque vulnerability and adverse events.}},
author = {{Mulholland, Megan}},
isbn = {{978-91-8021-492-6}},
issn = {{1652-8220}},
language = {{eng}},
number = {{2023:150}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Regulation of T cells in Atherosclerosis}},
url = {{https://lup.lub.lu.se/search/files/164905590/Kappa_Regulation_of_T_cells_in_Atherosclerosis_Mulholland_231027_pg_numb.pdf}},
year = {{2023}},
}