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

Svenja Meiler; Esther Smeets; Holger Winkels; Annelie Shami; Maria Fernanda Pascutti; Martijn A Nolte; Linda Beckers; Christian Weber; Norbert Gerdes; Esther Lutgens

doi:10.1161/ATVBAHA.116.307354

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

Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1748-52. doi: 10.1161/ATVBAHA.116.307354. Epub 2016 Jul 21.

Affiliations

¹ From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (S.M., E.S., H.W., A.S., L.B., E.L.); Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany (S.M., H.W., C.W., N.G., E.L.); Sanquin Research, Department of Hematopoiesis, Amsterdam, The Netherlands (M.F.P., M.A.N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (C.W.).
² From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (S.M., E.S., H.W., A.S., L.B., E.L.); Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany (S.M., H.W., C.W., N.G., E.L.); Sanquin Research, Department of Hematopoiesis, Amsterdam, The Netherlands (M.F.P., M.A.N.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (C.W.). [email protected].

PMID: 27444204
DOI: 10.1161/ATVBAHA.116.307354

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 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.

Keywords: GITR ligand; atherosclerosis; bone marrow; effector memory T cells; regulatory T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta / immunology
Aorta / metabolism*
Aorta / pathology
Aortic Diseases / genetics
Aortic Diseases / immunology
Aortic Diseases / metabolism
Aortic Diseases / prevention & control*
Atherosclerosis / genetics
Atherosclerosis / immunology
Atherosclerosis / metabolism
Atherosclerosis / prevention & control*
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
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
Glucocorticoid-Induced TNFR-Related Protein / metabolism*
Immunologic Memory
Interleukin-2 / genetics
Interleukin-2 / metabolism
Lymphocyte Activation*
Male
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Phenotype
Plaque, Atherosclerotic
Receptors, LDL / deficiency
Receptors, LDL / genetics
Severity of Illness Index
Signal Transduction
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism*
Thymus Gland / immunology
Thymus Gland / metabolism
Tumor Necrosis Factors / metabolism

Substances

CD3 Complex
Cholesterol, Dietary
Forkhead Transcription Factors
Foxp3 protein, mouse
Glucocorticoid-Induced TNFR-Related Protein
Interleukin-2
Receptors, LDL
Tnfrsf18 protein, mouse
Tnfsf18 protein, mouse
Tumor Necrosis Factors