Immunity
Volume 3, Issue 4, October 1995, Pages 407-415
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Article
Low avidity recognition of self-antigen by T cells permits escape from central tolerance

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Abstract

The immunodominant epitope of myelin basic protein, Ac1–9, is encephalitogenic in H-2u mice. We have previously demonstrated that this epitope displays low affinity for I-Au and have suggested that the avidity of T cell recognition in the thymus may be compromised, enabling autoreactive T cells to escape self-tolerance. We have addressed this hypothesis directly by constructing transgenic mice expressing an encephalitogenic T cell receptor (TCR). Parenteral admininstration of Ac1–9 had no discernable impact on developing thymocytes. In contrast, peptide analogs displaying far higher affinity for I-Au, provoked deletion of CD4+CD8+ cells and transient down-regulation of the TCR by mature CD4+ CD8 thymocytes. The use of analogs of intermediate affinity permitted a margin of error to be defined for the induction of tolerance and confirmed that the affinity of Ac1–9 lies well below the critical threshold.

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These authors contributed equally to this work.

Present address: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, England.

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Present address and address for correspondence: Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, England.