PD-1-mediated deletion induces tolerance of CD8 T cell response specific for H60 under helpless condition

Abstract H60 is a dominant minor H antigen, for which specific CD8 T cell response dominates over those for other minor H antigens in B6 anti-BALB.B response. The specific CD8 T cell response for H60 is CD4 help-dependent, as burst expansion of the specific cells during the primary and memory responses occurs only when CD4 T cell activation accompanies. When the CD4 help is not provided, primary expansion was limited and, then, recall expansion of the specific CD8 T cells is impaired even when the CD4 help is provided during the memory response. This tolerance phenomenon was ascribed to intrinsic property of H60-specific CD8 T cells activated under the helpless condition. The H60-specific CD8 T cells activated under helpless condition could develop into functionally active effector cells, migrating to inflamed sites. However, they were more prone to cell death with up-regulation of PD-1 on the H60-specific CD8 T cells activated under helpless condition. Recall expansion of H60-specific CD8 T was restored in the PD-1 deficient mice that had been primed under helpless condition, suggesting the significance of negative regulation by PD-1 in the tolerance induction of H60-specific CD8 T cell response after the helpless priming. These results will provide useful information for induction of tolerance after allogeneic transplantation.