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Constitutive GITR Activation Reduces Atherosclerosis by Promoting Regulatory CD4+ T-Cell Responses-Brief Report

Meiler, Svenja ; Smeets, Esther ; Winkels, Holger ; Shami, Annelie LU orcid ; Pascutti, Maria Fernanda ; Nolte, Martijn A ; Beckers, Linda ; Weber, Christian ; Gerdes, Norbert and Lutgens, Esther (2016) In Arteriosclerosis, Thrombosis, and Vascular Biology 36(9). p.52-1748
Abstract

OBJECTIVE: Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is expressed on CD4(+) effector memory T cells and regulatory T cells; however, its role on these functionally opposing cell types in atherosclerosis is not fully understood.

APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice (Ldlr(-/-)) were lethally irradiated and reconstituted with either bone marrow from B-cell-restricted Gitrl transgenic mice or from wild-type controls and fed a high-cholesterol diet for 11 weeks. Chimeric Ldlr(-/-) Gitrl(tg) mice showed a profound increase in both CD4(+) effector memory T cells and regulatory T cells in secondary lymphoid organs. Additionally, the number of regulatory T cells was... (More)

OBJECTIVE: Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is expressed on CD4(+) effector memory T cells and regulatory T cells; however, its role on these functionally opposing cell types in atherosclerosis is not fully understood.

APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice (Ldlr(-/-)) were lethally irradiated and reconstituted with either bone marrow from B-cell-restricted Gitrl transgenic mice or from wild-type controls and fed a high-cholesterol diet for 11 weeks. Chimeric Ldlr(-/-) Gitrl(tg) mice showed a profound increase in both CD4(+) effector memory T cells and regulatory T cells in secondary lymphoid organs. Additionally, the number of regulatory T cells was significantly enhanced in the thymus and aorta of these mice along with increased Gitrl and Il-2 transcript levels. Atherosclerotic lesions of Ldlr(-/-) Gitrl(tg) chimeras contained more total CD3(+) T cells as well as Foxp3(+) regulatory T cells overall, leading to significantly less severe atherosclerosis.

CONCLUSIONS: These data indicate that continuous GITR stimulation through B cell Gitrl acts protective in a mouse model of atherosclerosis by regulating the balance between regulatory and effector memory CD4(+) T cells.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Aorta/immunology, Aortic Diseases/genetics, Atherosclerosis/genetics, B-Lymphocytes/immunology, Bone Marrow Transplantation, CD3 Complex/metabolism, Cholesterol, Dietary, Disease Models, Animal, Forkhead Transcription Factors/metabolism, Genetic Predisposition to Disease, Glucocorticoid-Induced TNFR-Related Protein/genetics, Immunologic Memory, Interleukin-2/genetics, Lymphocyte Activation, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Phenotype, Plaque, Atherosclerotic, Receptors, LDL/deficiency, Severity of Illness Index, Signal Transduction, T-Lymphocytes, Regulatory/immunology, Thymus Gland/immunology, Tumor Necrosis Factors/metabolism
in
Arteriosclerosis, Thrombosis, and Vascular Biology
volume
36
issue
9
pages
52 - 1748
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:84979659120
  • pmid:27444204
ISSN
1524-4636
DOI
10.1161/ATVBAHA.116.307354
language
English
LU publication?
no
additional info
© 2016 American Heart Association, Inc.
id
9f395063-6e49-40bf-9b32-8ecd90ada691
date added to LUP
2025-01-22 14:50:01
date last changed
2025-07-10 17:42:52
@article{9f395063-6e49-40bf-9b32-8ecd90ada691,
  abstract     = {{<p>OBJECTIVE: Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is expressed on CD4(+) effector memory T cells and regulatory T cells; however, its role on these functionally opposing cell types in atherosclerosis is not fully understood.</p><p>APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice (Ldlr(-/-)) were lethally irradiated and reconstituted with either bone marrow from B-cell-restricted Gitrl transgenic mice or from wild-type controls and fed a high-cholesterol diet for 11 weeks. Chimeric Ldlr(-/-) Gitrl(tg) mice showed a profound increase in both CD4(+) effector memory T cells and regulatory T cells in secondary lymphoid organs. Additionally, the number of regulatory T cells was significantly enhanced in the thymus and aorta of these mice along with increased Gitrl and Il-2 transcript levels. Atherosclerotic lesions of Ldlr(-/-) Gitrl(tg) chimeras contained more total CD3(+) T cells as well as Foxp3(+) regulatory T cells overall, leading to significantly less severe atherosclerosis.</p><p>CONCLUSIONS: These data indicate that continuous GITR stimulation through B cell Gitrl acts protective in a mouse model of atherosclerosis by regulating the balance between regulatory and effector memory CD4(+) T cells.</p>}},
  author       = {{Meiler, Svenja and Smeets, Esther and Winkels, Holger and Shami, Annelie and Pascutti, Maria Fernanda and Nolte, Martijn A and Beckers, Linda and Weber, Christian and Gerdes, Norbert and Lutgens, Esther}},
  issn         = {{1524-4636}},
  keywords     = {{Animals; Aorta/immunology; Aortic Diseases/genetics; Atherosclerosis/genetics; B-Lymphocytes/immunology; Bone Marrow Transplantation; CD3 Complex/metabolism; Cholesterol, Dietary; Disease Models, Animal; Forkhead Transcription Factors/metabolism; Genetic Predisposition to Disease; Glucocorticoid-Induced TNFR-Related Protein/genetics; Immunologic Memory; Interleukin-2/genetics; Lymphocyte Activation; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Phenotype; Plaque, Atherosclerotic; Receptors, LDL/deficiency; Severity of Illness Index; Signal Transduction; T-Lymphocytes, Regulatory/immunology; Thymus Gland/immunology; Tumor Necrosis Factors/metabolism}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{52--1748}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Arteriosclerosis, Thrombosis, and Vascular Biology}},
  title        = {{Constitutive GITR Activation Reduces Atherosclerosis by Promoting Regulatory CD4+ T-Cell Responses-Brief Report}},
  url          = {{http://dx.doi.org/10.1161/ATVBAHA.116.307354}},
  doi          = {{10.1161/ATVBAHA.116.307354}},
  volume       = {{36}},
  year         = {{2016}},
}