Functional analysis of CD4+ CD25bright T cells in kidney transplant patients: improving suppression of donor-directed responses after transplantation

Abstract: Background: The role of CD4⁺ CD25^bright regulatory T cells (Treg) in controlling alloreactivity is established, but little is known whether antigen‐specific Treg are induced in fully immunosuppressed kidney transplant patients. Methods: The frequency and function of CD25^bright T cells of nine stable kidney transplant patients before and 0.5–2 yr after transplantation were measured. Patients received triple therapy consisting of cyclosporine, mycophenolate mofetil and prednisone. To investigate the influence of transplantation and immunosuppression on Treg function, we compared their suppressive capacities pre‐ and post‐transplantation using mixed lymphocyte reactions and kept the CD25^?/dim effector T‐cell (Teff) population constant. Results: After transplantation, the percentage of CD4⁺ CD25^bright T cells significantly decreased from 8.5% pre‐transplant to 6.9% post‐transplant (median, p = 0.05). However, the lower percentage of post‐transplant CD4⁺ CD25^bright T cells was not associated with reduced, but rather improved suppressor function of these cells. The proliferative response of pre‐transplant Teff to donor‐antigens was more profoundly suppressed by post‐transplant Treg than by pre‐transplant Treg (pre‐transplant 18% vs. post‐transplant 55% median, p = 0.03) and was comparable against third party antigens at a CD25^bright:CD25^?/dim ratio of 1:20. Conclusions: In immunosuppressed kidney transplant patients, the donor‐directed suppressive capacity of CD4⁺ CD25^bright regulatory T cells improved, which may contribute to the development of donor‐specific hyporesponsiveness against the graft.