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1
,
* Center for Immunology,
Department of Pathology, and
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
There is a paucity of knowledge concerning the immunologic sequelae that culminate in overt autoimmunity. In the present study, we have analyzed the factors that lead to disease in the model of autoimmunity, murine experimental autoimmune encephalomyelitis (EAE). EAE in H-2u mice involves autoreactive CD4+ T cells that are induced by immunization with the immunodominant N-terminal epitope of myelin basic protein. The affinity of this epitope for I-Au can be increased by substituting lysine at position 4 with tyrosine, and this can be used to increase the effective Ag dose. Paradoxically, high doses of Ag are poorly encephalitogenic. We have used quantitative analyses to study autoreactive CD4+ T cell responses following immunization of mice with Ag doses that are at the extremes of encephalitogenicity. A dose of autoantigen that is poorly encephalitogenic results in T cell hyperresponsiveness, triggering an anti-inflammatory feedback loop in which IFN-
plays a pivotal role. Our studies define a regulatory mechanism that serves to limit overly robust T cell responses. This feedback regulation has broad relevance to understanding the factors that determine T cell responsiveness.
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 grants from the National Institutes of Health (R01 AI/NS 42949), National Multiple Sclerosis Society (RG 2411), and Wadsworth Foundation. A.M. was supported by a Fellowship of the Fondo de Investigacion Sanitaria (BAE 00/5030 and 01/5037).
2 A.M. and S.P. contributed equally to this study.
3 Current address: Immunology Service, University Hospital "Virgen de la Arrixaca," El Palmar, Murcia, Spain.
4 Current address: Ophthalmology Institute of Alicante (VISSUM), c/Cabanal, Alicante, Spain.
5 Address correspondence and reprint requests to Dr. E. Sally Ward, Center for Immunology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9093. E-mail address: sally.ward{at}utsouthwestern.edu
6 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; LN, lymph node; MBP, myelin basic protein; pMHC, peptide-MHC; tg, transgenic.
This article has been cited by other articles:
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