Transplantation Tolerance in NF-κB-Impaired Mice Is Not Due to Regulation but Is Prevented by Transgenic Expression of Bcl-xL

Abstract

NF-κB is a key regulator of transcription after TCR and costimulatory receptor ligation. To determine the role of T cell-intrinsic NF-κB activation in acute allograft rejection, we used IκBαΔN-Tg mice (H-2b) that express an inhibitor of NF-κB restricted to the T cell compartment. We have previously shown that these mice permanently accept fully allogeneic (H-2d) cardiac grafts and secondary donor skin grafts, and that splenocytes from these tolerant mice have reduced alloreactivity when restimulated in vitro. These results were compatible with either deletion or suppression of allospecific T cells as possible mechanisms of tolerance. The aim of this study was to investigate the mechanism of transplant tolerance in these mice. IκBαΔN-Tg mice did not have increased numbers or function of CD4+CD25+ regulatory T cells either before or after cardiac transplantation. In addition, tolerance could not be transferred to fresh NF-κB-competent T cells and was not permissive for linked suppression to skin grafts sharing donor and third-party alloantigens, suggesting that dominant suppression is not the mechanism by which IκBαΔN-Tg mice achieve tolerance. In contrast, overexpression of the antiapoptotic protein Bcl-xL in T cells from IκBαΔN-Tg mice resulted in effective rejection of cardiac allografts and correlated with an increased frequency of splenocytes producing IFN-γ in response to alloantigen. Together, these results suggest that the death of alloreactive T cells may be partly responsible for the transplantation tolerance observed in mice with defective T cell-intrinsic NF-κB activation.