title: CTLA4-IgG ameliorates homocysteine-accelerated atherosclerosis by inhibiting T-cell overactivation in apoE(-/-) mice.
abstract: OBJECTIVE
  Cytotoxic T lymphocyte antigen 4 (CTLA4) exerts inhibitory effects on T-cell activation by competition with CD28. In this study, we investigated the effect of CTLA4-IgG on homocysteine (Hcy)-induced T-cell activation and potential signal pathways involved in atherosclerotic formation.
  
  
  RESULTS
  The CD28 signal was significantly amplified by Hcy treatment in splenic T cells and hyperhomocysteinaemia (HHcy)-accelerated plaques in apolipoprotein E-deficient (apoE(-/-)) mice. As a major competitor of CD28, CTLA4-IgG (abatacept) pretreatment, 100 μg/week, in apoE(-/-) mice could reverse 2- and 4-week HHcy-accelerated atherosclerosis. Furthermore, the membrane level of CTLA4 was decreased and the endocytosis level was increased by HHcy. Endocytosed CTLA4 molecules by Hcy were in large vesicles, colocalized with lysosomes and endosomes. Hcy-increased CTLA4 endocytosis and secretion of inflammatory cytokines in T cells were blocked by CTLA4-IgG and the PI3K inhibitor LY294002. Blocking the CD28 signal pathway in T cells significantly decreased Hcy-promoted macrophage migration.
  
  
  CONCLUSIONS
  These results illustrate a novel mechanism of CD28-dependent T-cell costimulation involved in HHcy-accelerated atherosclerosis, which extends the pharmacological application of CTLA4-IgG for atherosclerosis.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, Beijing 100191, PR China.
authors.forename: Kongyang
authors.initials: K
authors.lastname: Ma
authors.forename: Silin
authors.initials: S
authors.lastname: Lv
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Liu
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Luo
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.forename: Juan
authors.initials: J
authors.lastname: Feng
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
mesh_terms: D000069594:Abatacept; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism; D004705:Endocytosis; D005260:Female; D020138:Hyperhomocysteinemia / Q000150:complications*; D018796:Immunoconjugates / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D001057:Apolipoproteins E; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D000069594:Abatacept; D007371:Interferon-gamma