Feedback regulation of murine autoimmunity via dominant anti-inflammatory effects of interferon γ

Minguela, Alfredo, Pastor, Silvia, Mi, Wentao, Richardson, James A. and Ward, E. Sally (2007) Feedback regulation of murine autoimmunity via dominant anti-inflammatory effects of interferon γ. Journal of Immunology, 178 (1), 134-144.

Abstract

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-2^u mice involves autoreactive CD4⁺ T cells that are induced by immunization with the immunodominant N-terminal epitope of myelin bask protein. The affinity of this epitope for I-A^u can be increased by substituting lysine at position 4 with tyrosine, and this can be used to increase the elective Ag dose. Paradoxically, high doses of Ag are poorly encephalitegenic. 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-γ 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.

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Contributors

Author: E. Sally Ward

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