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

Abstract

AbstractTreating mice with an immunodominant T cell epitope from moth cytochrome c (MCC88–103) can induce T cell unresponsiveness under certain conditions of administration. In this report, we determined whether T cell tolerance to MCC88–103 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 MCC88–103-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 MCC88–103, 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.