The role of the allograft in the induction of donor-specific T cell hyporesponsiveness

Background. With adequate immunosuppression the majority of renal allografts are accepted, despite the exceptional vigour of the T cell alloimmune response. Previous work from this laboratory has demonstrated that this is accompanied by significant reductions in the precursor frequencies of anti-donor T cells. We have also shown that parenchymal cells are tolerogenic in vitro. We propose that the reduction in T cell frequencies may be due to the interaction between circulating T cells and potentially tolerogenic graft parenchymal cells. Primed/memory T cells (CD45RO(+)) are the only subset capable of reaching the allograft and therefore we would predict that T cell hyporesponsiveness would develop predominantly in the CD45RO(+) subset due to their trafficking properties. Methods. Frequencies of IL-2 secreting CD45RA(+) and CD45RO(+) CD4(+) T cells in response to donor and third party stimulator cells were estimated in a series of renal transplant recipients, both before and after transplantation. Results. There were highly significant reductions in the frequencies of donor-specific CD4(+)CD45RO(+) T cells, when adjusted to control for the generalised effects of immunosuppression. There were no significant alterations in the frequencies of donor-specific CD4(+)CD45RA(+) T cells. Conclusions. In renal transplant recipients, donor-specific CD4(+) T cell hyporesponsiveness occurs predominantly in CD4(+) CD45RO(+) T cells which is the subset capable of trafficking through the graft.