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CD4⁺ T Cell Expressed CD80 Regulates Central Nervous System Effector Function and Survival during Experimental Autoimmune Encephalomyelitis¹

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

CD80 expressed on the surface of APCs provides a positive costimulatory signal to naive CD4⁺ T cells during activation. Therefore, it was hypothesized that treatment of SJL mice with various forms of anti-CD80 mAb during remission from the acute phase of relapsing experimental autoimmune encephalomyelitis (R-EAE) would ameliorate disease progression. We previously reported that treatment of SJL mice with anti-CD80 Fab during R-EAE remission blocked activation of T cells specific for endogenous myelin epitopes, inhibiting epitope spreading and clinical disease progression; however, treatment with the native form of the same anti-CD80 mAb exacerbated disease progression. The current data show that intact anti-CD80 mAb binds both CNS-infiltrating CD4⁺ T cells and CD11c⁺ dendritic cells and that exacerbation of R-EAE directly correlates with increased survival and activity of myelin-specific CD4⁺ T cells, while the percentage of CD11c⁺ dendritic cells in the CNS and their APC activity was not altered. In vitro data show that cross-linking CD80 on the surface of CD4⁺ T cells activated in the presence of Th1-promoting cytokines increases the level of T cell activation, effector function, and survival by directly up-regulating the expression levels of transcripts for T-bet, IFN-, and Bcl-x_L. These findings indicate a novel regulatory role for CD80-mediated intracellular signals in CD4⁺ T cells and have important implications for using anti-costimulatory molecule mAb therapy in established autoimmune disease.

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. A.P.K. is supported by National Multiple Sclerosis Society Postdoctoral Fellowship Grant FG-1516-A-1.

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

³ Abbreviations used in this paper: DC, dendritic cell; MBP, myelin basic protein; MS, multiple sclerosis; PLP, myelin proteolipid protein; R-EAE, relapsing experimental autoimmune encephalomyelitis; Tg, transgenic.