The in vivo molecular and cellular interactions involved in peptide induced graft tolerance

Abstract

Intranasal (i.n.) administration of the class II restricted peptide, NAGFNSNRANSSRSS, encoded by the Dby gene (HY-AbDby) can induce tolerance to male skin grafts and haematopoietic cells in high responder B6 (H2b) female mice (Chai et al., 2004). i.n. administration of the single class II peptide is able to induce tolerance not only in B6 recipients that express two additional MHC Class I epitopes but also in (B6xCBA)F1 mice that express a further class II and two class I restricted HY peptide epitopes, a total of five. The aim of this project was to explore the mechanism(s) by which i.n. HY-AbDby peptide induces tolerance to male grafts. To do this gene expression in antigen specific T cells was analysed during both the tolerance induction phase and during the linked suppression phase, after male skin grafting. During tolerance induction HY-specific cells were found to upregulate the genes encoding FoxP3, PD-1, CTLA4 , IFN! and IL-13. This suggests that i.n. peptide induced a regulatory T cell population that may also modulate antigen presenting DCs. Following challenge with male cells, antigen specific CD8+ cells from rejecting mice were found to upregulate genes involved in cell killing such as granzyme B, FasL and cathepsin B. CD8+ cells from tolerant mice were not found to upregulate these genes. Furthermore, after male skin grafting antigen specific CD8+ T cells accumulated the graft draining lymph nodes. Taken together, the results presented in this thesis suggest that i.n. peptide induces a regulatory population of FoxP3+ CD4+ T cells that can prevent transplantation rejection by modulating dendritic cell function and preventing antigen specific CD8+ T cell from migrating from the graft draining lymph node.