The Protective Effect of CD8 +CD28 − T Suppressor Cells On The Acute Rejection Responses in Rat Liver Transplantation

Abstract

Regulatory T cells (Tr) or T-suppressor cells (Ts), which include CD4 +CD25 + T cells and CD8 +CD28 − T cells respectively, have been shown to be essential for the induction and maintenance of immune tolerance. We have investigated the effect of CD8 +CD28 − Ts and CD4 +CD25 + Tr on acute rejection responses in rat liver transplantation (OLT). Methods CD8 +CD28 − Ts/CD4 +CD25 + Tr were obtained from inbred and naïve rats that show spontaneous tolerance to OLT. Adoptive transfers were performed in acute rejection models of various strain combinations with survival times observed to evaluate suppressive effects. Donor-specific blood transfusion (DST) was used to induce CD8 +CD28 − Ts in naïve rats, which were assayed in vitro using carboxyfluorescein diacetate succinimidyl easter-labeled one-way mixed lymphocyte reactions. Secondary adoptive transfers of DST-induced CD8 +CD28 − Ts were also performed in an acute OLT rejection model. Results CD8 +CD28 − Ts from tolerant OLT model rats possessed immunosuppressive activity in allogeneic recipients; adoptive transfers of these cells alleviated the acute rejection responses. However, CD4 +CD25 + Tr derived from tolerant or naïve rats failed to do so. In vitro DST-induced CD8 +CD28 − Ts inhibited alloantigen T-cell responses in naïve syngeneic rats in an antigen-specific manner. Secondary adoptive transfer of DST-induced CD8 +CD28 −Ts further reduced acute rejection but not chronic rejection responses. Conclusions CD8 +CD28 − Ts cells protected allogeneic recipients from acute rejection in rat OLT. Furthermore, this activity was not present in CD4 +CD25 +Tr. DST was observed to be an effective method to generate functional CD8 +CD28 −Ts in naïve rats.