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Cross-Linking of CD80 on CD4⁺ T Cells Activates a Calcium-Dependent Signaling Pathway¹

Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611

CD80 expressed on the surface of APCs provides a positive costimulatory signal to naive CD4⁺ T cells via CD28 during activation. However, CD80 is also expressed on the surface of activated CD4⁺ T cells, and cross-linking CD80 on the surface of CD4⁺ T cells activated in the presence of Th1-promoting cytokines induces a direct up-regulation of T-bet, IFN-, and Bcl_(XL) expression in primary CD4⁺ T cells. The present data show that naive CD4⁺ T cells activated in Th1-promoting conditions in the presence of anti-CD80 mAb increase the level of IFN- produced by increasing the rate of IFN- mRNA transcription, which is supported by an increase in the level of T-bet phosphorylation and T-bet binding to the third intronic enhancer in the IFN- locus. Furthermore, anti-CD80 mAb-induced increase in IFN- expression and T-bet phosphorylation is dependent upon the activation of a Ca²⁺-dependent pathway as shown by anti-CD80 mAb-induced intracellular Ca²⁺ flux following CD80 cross-linking. These findings indicate a novel regulatory role for CD80-mediated intracellular signals in CD4⁺ T cells and have important implications for disease therapies using anti-costimulatory mAbs as use of an intact CD80 mAb may lead to CD80 cross-linking on activated T cells and enhanced proinflammatory cytokine production.

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 in part by U.S. Public Health Service, National Institutes of Health Grants NS-034819 and NS-026543, and by support from the Myelin Repair Foundation. J.R.P. is supported by National Multiple Sclerosis Society Postdoctoral Fellowship Grant FG-1667A1/2.

² Address correspondence and reprint requests to Dr. Stephen D. Miller, Department of Microbiology-Immunology, Northwestern University, Tarry 6-718, 303 E. Chicago Ave, Chicago, IL 60611. E-mail address: s-d-miller{at}northwestern.edu

³ Abbreviations used in this paper: R-EAE, relapsing experimental autoimmune encephalomyelitis; ChIP, chromatin immunoprecipitation; MS, multiple sclerosis.