Background. CD4
CD25

CD45RA
cells (naïve regulatory T cells [naïve-Tregs]) have been identified as a functionally
premature form of CD4
CD25


CD45RA cells (conventional-Tregs). However, their contribution to
transplant tolerance remains to be elucidated.
Method.Weexamined the frequency and the function of conventional and naive-Tregs in the peripheral blood derived
from operationally tolerant patients after pediatric living-donor liver transplant (Gr-tol ). The data were compared with
those of patients who were unable to be weaned off immunosuppression due to rejection (group-intolerance
[Gr-intol]), patients in the process of weaning immunosuppression (Gr-weaning) and healthy volunteers (grouphealthy
volunteers [Gr-vol]).
Results. In Gr-tol, the frequency of conventional-Tregs was significantly higher than that in Gr-vol and tended to be
higher than that in Gr-intol. The frequency of naive-Tregs was significantly decreased in Gr-intol versus those in
Gr-tol, -weaning, and -vol. In mixed lymphocyte reactions, donor-specific hyporesponsiveness of CD4
cells was
observed only in Gr-tol but not in the other groups. Depletion of conventional or naive-Tregs from CD4
cells
demonstrated that the suppressive properties of donor antigen-reactive conventional and naïve-Tregs were upregulated
compared with those of third-party antigen-reactive conventional and naïve-Tregs in Gr-tol only.
Conclusions. This is the first report providing detailed evidence that donor-specific naïve-Tregs were generated and
their suppressive properties were upregulated in the peripheral blood of tolerant patients, whereas their frequency was
downregulated in intolerant patients. Therefore, we speculate that not only conventional-Tregs play a role in Tx
tolerance but also the role of naïve-Tregs is critica.