MHC-derived allopeptide activates TCR-biased CD8 super( +) Tregs and suppresses organ rejection

In a rat heart allograft model, preventing T cell costimulation with CD40Ig leads to indefinite allograft survival, which is mediated by the induction of CD8 super( +)CD45RC super( lo) regulatory T cells (CD8 super( +)CD40Ig Tregs) interacting with plasmacytoid dendritic cells (pDC). The role of TCR-MHC-peptide interaction in regulating Treg activity remains a topic of debate. Here, the authors identified a donor MHC class II-derived peptide (Du51) that is recognized by TCR-biased CD8 super( +)CD40Ig Tregs and activating CD8 super( +)CD40Ig Tregs in both its phenotype and suppression of antidonor alloreactive T cell responses. RT1.A super( a6/Du51-specific CD8)sup + not equal to D40Ig Tregs were the most suppressive subset of the total Treg population, were essential for in vivo tolerance induction, and expressed a biased, restricted V beta 11-TCR repertoire in the spleen and the graft. Finally, they demonstrated that treatment of transplant recipients with the Du51 peptide resulted in indefinite prolongation of allograft survival. These results show that, CD8 super( +)CD40Ig Tregs recognize a dominant donor antigen, resulting in TCR repertoire alterations in the graft and periphery.