title: Thy28 protects against anti-CD3-mediated thymic cell death in vivo.
abstract: Apoptotic cell death plays a pivotal role in the development and/or maintenance of several tissues including thymus. Deregulated thymic cell death is associated with autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), a prototype murine model for analysis of human multiple sclerosis. Because Thy28 expression is modulated during thymocyte development, we tested whether Thy28 affects induction of EAE as effectively as antigen-induced thymocyte deletion using Thy28 transgenic (TG) mice. Thy28 TG mice showed partial resistance to anti-CD3 monoclonal antibody (mAb)-induced thymic cell death in vivo, as assessed by annexin V-expression and loss of mitochondrial membrane potential. The resistance to anti-CD3 mAb-induced cell death in Thy28 TG mice appeared to correlate with a decreased c-Jun N-terminal kinase phosphorylation and reduced down-regulation of Bcl-xL. Moreover, thymic hyperplasia was detected in Thy28 TG mice, although thymocyte development was unaltered. Development of peripheral lymphoid tissues including spleen and lymph nodes was also unaltered. Thy28 TG spleen T cells showed an increased production of IFN-γ, but not IL-17, in response to both anti-CD3 and anti-CD28 mAbs. Finally, Thy28 TG mice displayed accelerated induction of EAE as assessed by disease incidence, clinical score, and pathology following immunization with myelin oligodendrocyte glycoprotein compared with control WT mice. These findings suggest that modulation of Thy28 expression plays a crucial role in the determination of thymic cell fate, which may contribute to the development of EAE through proinflammatory cytokine production.
authors.affiliation: Department of Immunology and Intractable Immunology Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan, yuzz-t@tokyo-med.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Toyota
authors.forename: K
authors.initials: K
authors.lastname: Sudo
authors.forename: K
authors.initials: K
authors.lastname: Kojima
authors.forename: N
authors.initials: N
authors.lastname: Yanase
authors.forename: T
authors.initials: T
authors.lastname: Nagao
authors.forename: R H
authors.initials: RH
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Iobe
authors.forename: T
authors.initials: T
authors.lastname: Kuwabara
authors.forename: T
authors.initials: T
authors.lastname: Kakiuchi
authors.forename: J
authors.initials: J
authors.lastname: Mizuguchi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D017252:CD3 Complex / Q000276:immunology*; D016923:Cell Death; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D009687:Nuclear Proteins; C470953:Thy28 protein, mouse