title: Differential inhibition of autoreactive memory- and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 (sCTLA4), CTLA4Ig and LEA29Y.
abstract: Cytotoxic T lymphocyte antigen 4 (CTLA4) is a potent inhibitory co-stimulatory molecule believed to be involved in type 1 diabetes and other autoimmune diseases. An association has been reported of both mRNA expression and serum levels of the soluble splice variant of CTLA4 (sCTLA4) with type 1 diabetes. Furthermore, recombinant fusion proteins CTLA4Ig and LEA29Y have been proposed as therapies for type 1 diabetes. We studied the role of (s)CTLA4 in islet autoimmunity. Binding capacity of the proteins to antigen-presenting cells was determined by flow cytometry in competition and binding assays. Functionality of sCTLA4 as well as the therapeutic inhibitory fusion proteins CTLA4Ig and LEA29Y was measured in a dose-response lymphocyte stimulation test, using a panel of diabetes-associated T cell clones reactive to islet autoantigens. As controls, mixed lymphocyte reactions (MLR) were performed to assess functionality of these proteins in a primary alloreactive setting. All three CTLA4 molecules were able to bind to antigen-presenting cells and inhibit the expression of CD80/CD86. sCTLA4 was able to suppress proliferation of different committed autoreactive T cell clones in a dose-dependent manner, whereas CTLA4Ig and LEA29Y were not. Conversely, CTLA4Ig and LEA29Y, rather than sCTLA4, were able to suppress naive alloreactive proliferation in a MLR. Our results indicate a differential role for sCTLA4, CTLA4Ig and LEA29Y proteins in memory versus primary immune responses with implications for efficacy in intervention therapy.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: V A L
authors.initials: VA
authors.lastname: Huurman
authors.forename: W W J
authors.initials: WW
authors.lastname: Unger
authors.forename: B P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: M K
authors.initials: MK
authors.lastname: Oaks
authors.forename: A K
authors.initials: AK
authors.lastname: Chandraker
authors.forename: O T
authors.initials: OT
authors.lastname: Terpstra
authors.forename: B O
authors.initials: BO
authors.lastname: Roep
mesh_terms: D000069594:Abatacept; D000938:Antigen-Presenting Cells / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology*; D015551:Autoimmunity; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007108:Immune Tolerance; D018796:Immunoconjugates / Q000276:immunology*; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept