title: The CD28 related molecule ICOS: T cell modulation in the presence and absence of B7.1/2 and regulational expression in multiple sclerosis.
abstract: Costimulatory signals play a key role in regulating T cell activation and are believed to have decisive influence in the inciting and perpetuating cellular effector mechanisms in autoimmune diseases such as multiple sclerosis (MS). Inducible costimulator protein (ICOS), a recently identified member of the CD28-family, presumably affects the differentiation of Th1/Th2 cells after primary activation and modulates the immune response of effector/memory T cells. This study examines the expression and functional role of ICOS costimulation in healthy donors and patients with MS. After nonspecific or antigen-specific stimulation, ICOS is preferentially expressed on CD4 Th2-T cells. ICOS-costimulation affects the production of Th1 and Th2 cytokines both in the absence and presence of B7/CD28 costimulation, thus suggesting that ICOS costimulation can modulate cytokine secretion also in a CD28-independent manner. Levels of constitutive and inducible ICOS expression on human T cell subsets from peripheral blood were quantified in healthy donors and patients with MS. Constitutive expression of ICOS on T cells varies between 0.1% and 42.3%. There were no significant differences between both groups in the baseline expression or inducibility of ICOS on CD4 or CD8 T cells. ICOS expression could be demonstrated on CSF T lymphocytes in patients with acute MS relapses but was not elevated compared with peripheral blood. In essence we show that ICOS is upregulated on human T cells after stimulation and can modulate both Th1 and Th2 cytokine production in the absence and presence of B7-costimulation. In MS patients we demonstrate the functionality of the ICOS costimulatory pathway. Potential implications of ICOSL/ICOS interactions for MS immunopathogenesis are discussed.
authors.affiliation: Department of Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, Tübingen, D-72076, Germany. heinz.wiendl@uni-tuebingen.de
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Oliver
authors.initials: O
authors.lastname: Neuhaus
authors.forename: Matthias
authors.initials: M
authors.lastname: Mehling
authors.forename: Sabine
authors.initials: S
authors.lastname: Wintterle
authors.forename: Bettina
authors.initials: B
authors.lastname: Schreiner
authors.forename: Meike
authors.initials: M
authors.lastname: Mitsdoerffer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wienhold
authors.forename: Robert
authors.initials: R
authors.lastname: Weissert
authors.forename: Johannes
authors.initials: J
authors.lastname: Wessels
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Eva
authors.initials: E
authors.lastname: Tolosa
authors.forename: Arthur
authors.initials: A
authors.lastname: Melms
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis* / Q000134:cerebrospinal fluid / Q000235:genetics / Q000502:physiology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology*; D002460:Cell Line; D018920:Coculture Techniques; D005260:Female; D005434:Flow Cytometry; D000068717:Glatiramer Acetate; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007739:L Cells; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D008562:Membrane Glycoproteins; D010455:Peptides; D019707:Receptors, Chemokine; D015847:Interleukin-4; D000068717:Glatiramer Acetate; D016899:Interferon-beta; D007371:Interferon-gamma