Low avidity recognition of self-antigen by T cells permits escape from central tolerance

GY Liu, PJ Fairchild, RM Smith, JR Prowle, D Kioussis… - Immunity, 1995 - cell.com
GY Liu, PJ Fairchild, RM Smith, JR Prowle, D Kioussis, DC Wraith
Immunity, 1995cell.com
The immunodominant epitope of myelin basic protein, Ad-9, is encephalitogenic in H-2”
mice. We have previously demonstrated that this epitope displays low affinity for IA” 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 encephalitogenie T cell receptor
(TCR). Parenteral admininstration of Acl-9 had no discernable impact on developing …
Summary
The immunodominant epitope of myelin basic protein, Ad-9, is encephalitogenic in H-2” mice. We have previously demonstrated that this epitope displays low affinity for IA” 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 encephalitogenie T cell receptor (TCR). Parenteral admininstration of Acl-9 had no discernable impact on developing thymocytes. In contrast, peptide analogs displaying far higher affinity for IA”, 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 Acl-9 lies well below the critical threshold.
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