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.

CARMA1 Regulation of Regulatory T Cell Development Involves Modulation of Interleukin-2 Receptor Signaling

“…However, how NF-B exerts its function in Treg development is still incompletely understood. A previous study suggests that the IB␣⌬Ntg mice do not show reduced frequency of CD4 ϩ CD25 ϩ T cells in the periphery (34). Consistently, our current study reveals that the IB␣⌬Ntg mice have normal frequency of peripheral Tregs and moderately reduced frequency of thymic Tregs.…”

NF-κB and the regulation of hematopoiesis

“…85 The graft tolerance of these mice seems to be because of T-cell deletion as overexpression of Bcl-xL reinstated rejection of the cardiac allograft. 86 Several strategies to block NF-kB have been under investigation in this disease. NF-kB decoy oligonucleotides have been shown to have a beneficial effect on heart transplantation, 87 whereas pyrrolidine dithiocarbamate (PDTC, an NF-kB inhibitor) seems to improve liver graft transplantation.…”

Role of Natural Killer Cell Subsets in Cardiac Allograft Rejection

“…The abdominal heterotopic cardiac transplantation protocol was performed as previously described (16).…”