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Loss of IFN- Enables the Expansion of Autoreactive CD4⁺ T Cells to Induce Experimental Autoimmune Encephalomyelitis by a Nonencephalitogenic Myelin Variant Antigen¹

Joseph J. Sabatino, Jr.^*, John Shires, John D. Altman^*,, Mandy L. Ford and Brian D. Evavold^2,*

^* Department of Microbiology and Immunology and Department of Surgery, Emory University, Atlanta, GA 30322; and Emory Vaccine Research Center, Atlanta, GA 30329

MHC variant peptides are analogues of immunogenic peptides involving alterations of the MHC-binding residues, thereby altering the affinity of the peptide for the MHC molecule. Recently, our laboratory demonstrated that immunization of WT B6 mice with 45D, a low-affinity MHC variant peptide of MOG_35–55, results in significantly attenuated experimental autoimmune encephalomyelitis (EAE), yet IFN- production is comparable to myelin oligodendrocyte glycoprotein (MOG)_35–55-immunized mice. In light of these findings, we asked whether IFN- was required for the reduced encephalitogenicity of the weak ligand 45D in EAE. In this study, we report that immunization of mice deficient in IFN- or its receptor with 45D exhibit significant EAE signs compared with 45D-immunized wild-type B6 mice. Moreover, 45D-immunized IFN-^–/– and IFN-R^–/– mice demonstrate MOG tetramer-positive CD4⁺ T cells within the CNS and display substantial numbers of MOG-specific CD4⁺ T cells in the periphery. In contrast, wild-type mice immunized with 45D exhibit reduced numbers of MOG-specific CD4⁺ T cells in the periphery and lack MOG tetramer- positive CD4⁺ T cells in the CNS. Importantly, the increased encephalitogenicity of 45D in mice lacking IFN- or IFN-R was not due to deviation toward an enhanced IL-17-secreting phenotype. These findings demonstrate that IFN- significantly attenuates the encephalitogenicity of 45D and are the first to highlight the importance of IFN- signaling in setting the threshold level of responsiveness of autoreactive CD4⁺ T cells to weak ligands.

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 National Institutes of Health Grant AI056017.

² Address correspondence and reprint requests to Dr. Brian D. Evavold, Department of Microbiology and Immunology, Emory University, 1510 Clifton Road, Atlanta, GA 30322. E-mail address: evavold{at}microbio.emory.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; APL, altered peptide ligand; MOG, myelin oligodendrocyte glycoprotein; 7-AAD, 7-aminoactinomycin D; LN, lymph node; WT, wild type.