title: Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis.
abstract: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8(+) T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8(+) T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8(+) T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8(+) T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226(high)CD8(+) T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226(+)CD8(+) T cells produced higher amount of various cytokines than CD226(-) ones, and CD226(high)CD8(+) T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8(+) T cells against HUVECs. Finally, the neutralization of CD226 in CD8(+) T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8(+) T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ayano
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan; tsukamot@intmed1.med.kyushu-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Department of Hematology, National Kyushu Medical Center, Fukuoka 810-8563, Japan;
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kohno
authors.affiliation: Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki 880-8510, Japan;
authors.forename: Naoyasu
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan;
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mitoma
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan;
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Akahoshi
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan;
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Arinobu
authors.affiliation: Clinical Education Center, Kyushu University Hospital, Fukuoka 812-8582, Japan; and.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.affiliation: Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu 874-0836, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Horiuchi
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology*; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis; D007564:Japan; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012595:Scleroderma, Systemic / Q000276:immunology / Q000473:pathology*; D015533:Transcriptional Activation / Q000276:immunology; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D016207:Cytokines; D018793:Interleukin-13