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* Department of Microbiology and Immunology, Emory University School of Medicine,
Coulter Department of Biomedical Engineering, and
Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
Our lab has demonstrated that encephalitogenic T cells can be effectively anergized by treatment with MHC variant peptides, which are analogues of immunogenic peptides containing an amino acid substitution at an MHC anchor residue. The MHC variant peptide of myelin oligodendrocyte glycoprotein (MOG)35–55 proves an effective treatment as it does not induce symptoms of experimental autoimmune encephalomyelitis and fails to recruit macrophages or MOG35–55-specific T cells to the CNS. In this study, we sought to characterize the signaling pathways required for the induction of anergy by building upon the observations identifying the tyrosine phosphatase SHP-1 as a critical regulator of T cell responsiveness. Motheaten viable heterozygous mice, which contain a mutation in the SHP-1 gene resulting in a reduction in functional SHP-1, were challenged with MOG35–55 or the MOG35–55 MHC variant 45D. These mice display symptoms of experimental autoimmune encephalomyelitis upon immunization with MHC variant peptide and have significant CNS infiltration of tetramer-positive CD4+ cells and macrophages, unlike B6 mice challenged with the variant peptide. The effects of SHP-1 are directly on the T cell as Motheaten viable heterozygous mice autoreactive T cells are not anergized in vitro. Lastly, we demonstrate no distinguishable difference in the initial interaction between the TCR and agonist or MHC variant. Rather, an unstable interaction between peptide and MHC attenuates the T cell response, seen in a decreased half-life relative to MOG35–55. These results identify SHP-1 as a mediator of T cell anergy induced by destabilized peptide:MHC complexes.
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 NIH R01 AI 056017 and National Multiple Sclerosis Society Grant RG4047-A-3 (to B.D.E.), and NIH R01 AI38282 and AI060799 (to C.Z.).
2 H.A.W. and C.D.B. are co-first authors.
3 Address correspondence and reprint requests to Dr. Brian D. Evavold, Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. E-mail address: evavold{at}microbio.emory.edu
4 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; PLP, proteolipid protein; MOG, myelin oligodendrocyte glycoprotein; APL, altered peptide ligand; me-v, Motheaten viable.
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