title: A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production.
abstract: Immune aging results in diminished adaptive immunity and increased risk for autoimmunity. We previously reported a unique PD-1(+) CD44(high)CD4(+) T cell population that increases with age in normal mice. In this study, we indicate that the age-dependent PD-1(+) CD44(high)CD4(+) T cells develop as unique T follicular (TF) cells in a B cell-dependent manner and consist of two subpopulations, as follows: CD153(+) cells preferentially secreting abundant osteopontin on TCR stimulation and CD153(-) cells that are apparently TCR anergic. These unique TF cells with essentially similar features increase much earlier and are accumulated in the spontaneous germinal centers (GCs) in lupus-prone female BWF1 (f-BWF1) mice. These TF cells showed characteristic cell-senescence features and developed in association with extensive CD4(+) T cell proliferation in vivo, suggesting replicative senescence. Although the CD153(+) TF cells were defective in proliferation capacity, they were quite stable and specifically responded to self GC-B cells to secret abundant osteopontin, which inhibited B cell receptor-induced GC-B cell apoptosis in f-BWF1 mice. Transfer of CD153(+) PD-1(+) CD4(+) T cells promoted the growth of spontaneous GCs, whereas administration of anti-osteopontin Ab suppressed GC enlargement and anti-nuclear Ab production and ameliorated clinical lupus nephritis of f-BWF1 mice. Current results suggest that senescent CD153(+) TF cells generated as a consequence of extensive endogenous CD4(+) T cell proliferation play an essential, if not sufficient, role in lupus pathogenesis in lupus-prone genetic background and may also contribute to an increased autoimmunity risk with age.
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Suhail
authors.initials: S
authors.lastname: Tahir
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; and.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Harumi
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Joe
authors.initials: J
authors.lastname: Inoue
authors.affiliation: Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hamazaki
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; and.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hattori
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; minato@imm.med.kyoto-u.ac.jp.
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D053285:CD30 Ligand / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D016922:Cellular Senescence / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D008181:Lupus Nephritis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D053495:Osteopontin / Q000096:biosynthesis*; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D053285:CD30 Ligand; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D053495:Osteopontin