title: T-cell immunoglobulin and mucin domain 3 acts as a negative regulator of atherosclerosis.
abstract: OBJECTIVE
  Atherosclerosis is a chronic autoimmune-like disease in which lipids and fibrous elements accumulate in the arterial blood vessels. T cells are present within atherosclerotic plaques, and their activation is partially dependent on costimulatory signals, which can either provide positive or negative signals that promote T-cell activation or limit T-cell responses, respectively. T-cell immunoglobulin and mucin domain 3 (Tim-3) is a coinhibitory type 1 transmembrane protein that affects the function of several immune cells involved in atherosclerosis, such as monocytes, macrophages, effector T cells, and regulatory T cells. In the present study, we determined the role of Tim-3 in the development of atherosclerosis.
  
  
  RESULTS
  Western-type diet-fed low-density lipoprotein receptor-deficient (LDLr(-/-)) mice were treated with an anti-Tim-3 antibody for 3 and 8 weeks. Anti-Tim-3 administration increased fatty streak formation with 66% and increased atherosclerotic plaque formation after 8 weeks with 35% in the aortic root and with 50% in the aortic arch. Furthermore, blockade of Tim-3 signaling increased percentages of circulating monocytes with 33% and lesional macrophages with 20%. In addition, anti-Tim-3 administration increased CD4(+) T cells with 17%, enhanced their activation status, and reduced percentages of regulatory T cells with 18% and regulatory B cells with 37%.
  
  
  CONCLUSIONS
  It is known that Tim-3 acts as a negative regulator of both innate and adaptive immune responses, and in the present study, we show that anti-Tim-3 treatment augments lesion development, accompanied by an increase in the number of monocytes/macrophages and CD4(+) T cells and by decreased regulatory T cells and regulatory B cells.
authors.affiliation: From the Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (A.C.F., I.A.R., L.W., V.F., M.N.D.t.B., S.C.A.d.J., P.J.v.S., I.B., J.K., G.H.M.v.P.); Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (S.C.A.d.J.); and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan (H.Y., H.A.).
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Foks
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Ran
authors.forename: Loes
authors.initials: L
authors.lastname: Wasserman
authors.forename: Vanessa
authors.initials: V
authors.lastname: Frodermann
authors.forename: Mariëtte N D
authors.initials: MN
authors.lastname: Ter Borg
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Santbrink
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.forename: Gijs H M
authors.initials: GH
authors.lastname: van Puijvelde
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D001011:Aorta / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism*; D060151:B-Lymphocytes, Regulatory / Q000276:immunology; D000072597:Hepatitis A Virus Cellular Receptor 2; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D058226:Plaque, Atherosclerotic / Q000276:immunology / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D011991:Receptors, Virus
keywords: T cells; Tim-3; atherosclerosis; immunology; inflammation