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Termination of Peripheral Tolerance to a T Cell Epitope by Heteroclitic Antigen Analogues¹

Ulrich Zügel^*, Rongfang Wang^*, Grace Shih^*, Alessandro Sette, Jeff Alexander and Howard M. Grey^2,*

^* La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; and Cytel Corporation, San Diego, CA 92121

Treating mice with an immunodominant T cell epitope from moth cytochrome c (MCC_88–103) can induce T cell unresponsiveness under certain conditions of administration. In this report, we determined whether T cell tolerance to MCC_88–103 in adult animals can be overcome by immunization with cross-reactive analogues of the tolerizing Ag. A panel of analogues of the tolerogen were tested for their capacity to terminate the tolerant state following in vivo immunization. As analyzed by their stimulatory capacity for a representative MCC_88–103-specific T cell clone, this panel covered a wide range of cross-reactivity, including nonantigenic, antagonistic, weakly, and strongly antigenic peptides. Interestingly, only heteroclitic analogues, as measured in vitro by their enhanced antigenicity for the T cell clone that was specific for MCC_88–103, were capable of breaking tolerance. Thus, an immune response to the cross-reactive, heteroclitic analogues of tolerized self Ags may represent a mechanism by which Ag molecular mimicry operates.

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