The Possible Function And Mechanism Of Transcription Factor Csl/rbp-j In Acute Allograft Rejection

Acute allograft rejection (AAR) involves not only the innate but also the adopted immune systems. Acute allograft rejection is thought to be one of the most important risk factors for late graft loss To be a critical pathway in peripheral T-cell differentiation and function, Notch signaling is a potential therapeutic target to modulate AAR, but its role in alloimmune responses has not been fully addressed. By using fully MHC-mismatched allograft transplantation model,just as skin transplantation and cervical heterotopic heart transplantation,and T-cell specific RBP-J deficient mice, we investigated the role of Notch/RBP-J pathway in alloimmune responses in vivo and in vitro. Acute allograft rejection was significantly accelerated in RBP-J deficient mice compared with the wild-type controls, i.e. C57BL/6, as demonstrated by the marked reduction in graft survival. The reduction in graft survival was associated with augmented alloantigen specific T-cell proliferation and increased number of Th1, Th2, and Th17 cells in the RBP-J deficient recipient mice. Furthermore, although the frequency of CD4~+CD25~+Foxp3~+ Tregs was intact in RBP-J knockout recipients, their ability to suppress Teff responses in vitro were significantly dampened. These findings suggest that Notch/RBP-J pathway may attenuate acute allograft rejection by suppressing in vivo expansion of alloreactive T-cell proliferation and facilitating CD4~+CD25~+ Treg suppression ability, indicating that Notch pathway could be exploited to limit T-cell-mediated acute allograft rejection.