*Purpose: The present study aimed to investigate the role of BTLA in the progress of acute rejection after kidney transplantation.

*Methods: In human allograft renal transplanted recipients with biopsy-proven acute rejection (BPAR) or stable allograft function, as well as healthy control, the expression of BTLA was measured by flow cytometry, and immunohistochemistry (IHC) staining. Immunofluorescence and flow cytometer were respectively conducted to assess the immune status among allograft renal transplanted recipients. ELISA was performed to examine the release of inflammatory cytokines. In rat allograft renal transplantation model, results of HE staining were used to assess the pathologic characteristic of acute rejection in renal tissues with or without BTLA overexpression. IHC, western blot and qRT-PCR were performed to detect the BTLA expression in rat allograft renal samples. Mixed lymphocyte reaction (MLR) was also conducted to confirm the effect of BTLA on T cell activation and proliferation. Finally, western blot was adopted to explore the function of the transcription factors of T cell receptor (TCR) downstream signal pathways in acute rejection.

*Results: Flow cytometry showed BTLA expression on peripheral CD3+ T lymphocytes of BPAR recipients was significantly decreased compared with the stable group (P<0.01). In rat allogeneic renal transplantation model, acute rejection was observed obviously from 3d to 7d after transplantation, and the BTLA expression in grafts decreased at the early stage in acute rejection. Remarkably, overexpression of BTLA was found to significantly inhibit the progress of acute rejection, and regulate post-operative immune status, and prolong renal allograft survival (hazard ratio=0.25, 95% confidence interval: 0.07-0.85). Besides, BTLA overexpression could directly suppress T cells proliferation in MLR culture. Moreover, BTLA overexpression has significantly suppressed interleukin (IL)-2 and IFN-γ production, and increased IL-4 and IL-10 production in vivo and in vitro. In addition, vital factors of signal pathways including mitogen-activated protein kinase (MAPK), NF-κB and the nuclear factor of activated T cells (NFAT) have been significantly repressed by BTLA overexpression.

*Conclusions: BTLA overexpression could suppress acute rejection and regulate allogeneic responses of kidney transplant through regulating TCR downstream signaling pathways and inflammatory cytokines production, and improve long-term graft outcomes.

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