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High IFN- Production of Individual CD8 T Lymphocytes Is Controlled by CD152 (CTLA-4)¹

Pushpa Pandiyan^2,3,*, J. Kolja E. Hegel^3,*, Manuela Krueger, Dagmar Quandt^* and Monika C. Brunner-Weinzierl^4,*

^* Charité-Universitätsmedizin Berlin, Deutsches Rheumaforschungszentrum, Berlin, Germany; and Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany

CD8 T cell expansion and cytokine production is needed to generate an effective defense against viral invasion of the host. These features of CD8 T lymphocytes are regulated, especially during primary responses, by positive and negative costimulation. We show in this study that surface expression of CD152 is highly up-regulated on activated CD8 T lymphocytes during primary immune responses, suggesting a prominent regulatory role. Indeed, production of the proinflammatory cytokine IFN-, but not TNF-, by CD8 T cells was inhibited by CD152 engagement. The inhibition was regulated independent of proliferation and IL-2 production, but dependent on the quality of the TCR signaling. We show that signals induced by CD152 on activated CD8 T lymphocytes reduce the frequency of IFN-^high-expressing cells. Our data also show that in activated CD8 T cells, the CD152-mediated inhibition of cytokine production is more pronounced than inhibition of their proliferation.

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 the Gemeinnützige Hertie-Stiftung (to M.C.B.W.), Grant Deutsche Forschungsgemeinschaft Br1860/3 (to M.C.B.W.), NaFÖG Grant of Berlin (to P.P.), and a grant from Charité-Universitätsmedizin Berlin (to J.K.E.H.).

² Current address: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

³ P.P. and J.K.E.H. contributed equally to this work.

⁴ Address correspondence and reprint requests to Dr. Monika C. Brunner-Weinzierl, Molecular Immunology, Deutsches Rheuma-Forschungszentrum, Schumannstrasse 21/22, Berlin, Germany. E-mail address: brunner{at}drfz.de

⁵ Abbreviations used in this paper: WT, wild type; KO, knockout; MFI, mean fluorescence intensity; neg, negative.

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