title: Engagement of CD44 up-regulates Fas ligand expression on T cells leading to activation-induced cell death.
abstract: Activation-induced cell death (AICD) plays a pivotal role in self-tolerance by deleting autoreactive T cells, but a defect of AICD results in expansion of autoreactive T cells and is deeply involved in the pathogenesis of rheumatoid arthritis. Although the process of AICD is mainly mediated by Fas Ligand (FasL)/Fas signaling, it remains unclear what induces FasL expression on T cells. In the present study, we found that CD44 was the most potent stimulator of FasL expression on human peripheral T cells. CD44 cross-linking rapidly up-regulated FasL expression on the T cell surface by delivery from the cytoplasm without new FasL protein synthesis. This up-regulation of FasL was mediated by activation of a tyrosine kinase, IP3 receptor-dependent Ca(2+) mobilization and actin cytoskeletal rearrangements. Furthermore, AICD induced by CD3 restimulation was inhibited by hyaluronidase as well as by soluble Fas, indicating an interaction between membrane-bound hyaluronan and the cell surface CD44 was involved in the up-regulation of FasL expression on T cells and subsequent AICD. We therefore propose that the engagement of CD44 on T cells can eliminate autoreactive T cells by expression of FasL and FasL-mediated AICD.
authors.affiliation: Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. kaz_n@saitama-med.ac.jp
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakano
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Saito
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Mine
authors.forename: Sho
authors.initials: S
authors.lastname: Matsushita
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D015551:Autoimmunity; D020013:Calcium Signaling; D003432:Cross-Linking Reagents; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008213:Lymphocyte Activation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017634:Self Tolerance; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C497483:CD44 protein, human; D003432:Cross-Linking Reagents; D053222:Fas Ligand Protein; D018960:Hyaluronan Receptors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012333:RNA, Messenger; D006820:Hyaluronic Acid; D011505:Protein-Tyrosine Kinases