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Intrinsic and Induced Regulation of the Age-Associated Onset of Spontaneous Experimental Autoimmune Encephalomyelitis¹

Hong Zhang^*, Joseph R. Podojil^*, Xunrong Luo and Stephen D. Miller^2,*

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

Multiple sclerosis is characterized by perivascular CNS infiltration of myelin-specific CD4⁺ T cells and activated mononuclear cells. TCR transgenic mice on the SJL background specific for proteolipid protein (PLP)_139–151 develop a high incidence of spontaneous experimental autoimmune encephalomyelitis (sEAE). We examined the intrinsic mechanisms regulating onset and severity of sEAE. CD4⁺ T cells isolated from the cervical lymph nodes, but not spleens, of diseased 5B6 transgenic mice are hyperactivated when compared with age-matched healthy mice and produce both IFN- and IL-17, indicating that the cervical lymph node is the initial peripheral activation site. The age-associated development of sEAE correlates with a decline in both the functional capacity of natural regulatory T cells (nTregs) and in PLP_139–151-induced IL-10 production and a concomitant increase in IL-17 production. Anti-CD25-induced inactivation of nTregs increased the incidence and severity of sEAE. Conversely, induction of peripheral tolerance via the i.v. injection of PLP_139–151-pulsed, ethylcarbodiimide-fixed APCs (PLP_139–151-SP) inhibited the development of clinical disease concomitant with increased production of IL-10 and conversion of Foxp3⁺ Tregs from CD4⁺CD25^– progenitors. These data indicate that heterogeneous populations of Tregs regulate onset of sEAE, and that induction of peripheral tolerance can be exploited to prevent/treat spontaneous 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 by National Institutes of Health R01 Grants NS-026543 and NS-048411, National Multiple Sclerosis Society Grants RG 3793-A-7 and RG 3965-A-8, and a grant from the Myelin Repair Foundation.

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

³ Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; Tg, transgenic; MBP, myelin basic protein; PLP, proteolipid protein; sEAE, spontaneous experimental autoimmune encephalomyelitis; SPF, specific pathogen-free; Treg, regulatory T cell; nTreg, natural Treg; iTreg, induced Treg; 5B6 Tg, 5B6 PLP_139–151 TCR Tg; cLN, cervical lymph node; ECDI, ethylcarbodiimide; Ag-SP, Ag-splenocytes; DTH, delayed-type hypersensitivity.

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