Differential inhibition of autoreactive memory- and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 (sCTLA4), CTLA4Ig and LEA29Y

• Published in: Clinical and experimental immunology 2007-12, Vol.150 (3), p.487-493
• Main Authors: Huurman, V.A.L, Unger, W.W.J, Koeleman, B.P.C, Oaks, M.K, Chandraker, A.K, Terpstra, O.T, Roep, B.O
• Format: Article
• Language: English
• Subjects: Abatacept; alloimmunity; Antigen-Presenting Cells - metabolism; Antigens, CD - immunology; Antigens, Differentiation - immunology; Autoimmunity; Cell Proliferation; CTLA-4 Antigen; CTLA4Ig; Diabetes Mellitus, Type 1 - immunology; Dose-Response Relationship, Immunologic; Humans; Immune Tolerance; Immunoconjugates - immunology; Immunologic Memory; insulin-dependent diabetes mellitus; Lymphocyte Activation - immunology; Lymphocyte Culture Test, Mixed; soluble CTLA4; T-Lymphocytes - immunology; Translational Studies; type 1 diabetes
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2007.03513.x

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.