title: Constitutive GITR Activation Reduces Atherosclerosis by Promoting Regulatory CD4+ T-Cell Responses-Brief Report.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.).
authors.forename: Svenja
authors.initials: S
authors.lastname: Meiler
authors.affiliation: 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.).
authors.forename: Esther
authors.initials: E
authors.lastname: Smeets
authors.affiliation: 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.).
authors.forename: Holger
authors.initials: H
authors.lastname: Winkels
authors.affiliation: 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.).
authors.forename: Annelie
authors.initials: A
authors.lastname: Shami
authors.affiliation: 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.).
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Pascutti
authors.affiliation: 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.).
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Nolte
authors.affiliation: 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.).
authors.forename: Linda
authors.initials: L
authors.lastname: Beckers
authors.affiliation: 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.).
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: 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.).
authors.forename: Norbert
authors.initials: N
authors.lastname: Gerdes
authors.affiliation: 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.). e.lutgens@amc.nl.
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D017252:CD3 Complex / Q000378:metabolism; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000378:metabolism*; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012720:Severity of Illness Index; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D002791:Cholesterol, Dietary; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; D011973:Receptors, LDL; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors
keywords: GITR ligand; atherosclerosis; bone marrow; effector memory T cells; regulatory T cells