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Surface CD152 (CTLA-4) Expression and Signaling Dictates Longevity of CD28^null T Cells¹

Holger Hoff, Karin Knieke^2,*,, Zulema Cabail^2,*,, Heike Hirseland, George Vratsanos, Gerd-Rüdiger Burmester, Gerhard Jorch^*, Steven G. Nadler, Barbara Bröker, Katrin Hebel^* and Monika C. Brunner-Weinzierl^3,*,

^* Department of Pediatrics, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany; Deutsches Rheuma-Forschungszentrum Berlin und Klinik für Innere Medizin mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité-Universitätsmedizin Berlin, Berlin, Germany; Bristol-Myers Squibb, Princeton, NJ 08543; and Institut für Immunologie und Transfusionsmedizin, Universität Greifswald, Greifswald, Germany

CD28^null T cells are a highly enriched subset of proinflammatory T cells in patients with autoimmune diseases that are oligoclonal and autoreactive. In this study, we analyzed the role of CD152 signaling on the longevity of human CD28^null T cells. Using a sensitive staining method for CD152, we show that human CD4⁺CD28^null and CD8⁺CD28^null T cells rapidly express surface CD152. Serological inactivation of CD152 using specific Fab or blockade of CD152 ligands using CTLA-4Ig in CD4⁺CD28^null and CD8⁺CD28^null T cells enhances apoptosis in a Fas/FasL-dependent manner. CD152 cross-linking on activated CD28^null cells prevents activation-induced cell death as a result of reduced caspase activity. Apoptosis protection conferred by CD152 is mediated by phosphatidylinositol 3'-kinase-dependent activation of the kinase Akt, resulting in enhanced phosphorylation and thereby inhibition of the proapoptotic molecule Bad. We show that signals triggered by CD152 act directly on activated CD28^null T lymphocytes and, due to its exclusive expression as a receptor for CD80/CD86 on CD28^null T cells, prevention of CD152-mediated signaling is likely a target mechanism taking place during therapy with CTLA-4Ig. Our data imply strongly that antagonistic approaches using CD152 signals for chronic immune responses might be beneficial.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Bristol-Myers Squibb and Deutsche Forschungsgemeinschaft Br1680/3-4.

² K.K. and Z.C. contributed equally.

³ Address correspondence and reprint requests to Dr. Monika C. Brunner-Weinzierl; Department of Pediatrics; University Hospital, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44; 39120 Magdeburg, Germany. E-mail address: monika.brunner-weinzierl{at}med.ovgu.de

⁴ Abbreviations used in this paper: RA, rheumatoid arthritis; AICD, activation-induced cell death; FasL, Fas ligand; PI3'K, phosphatidylinositol 3'-kinase; PI, propidium iodide; PS, phosphatidylserine.