Abstract
T cells play a critical role in acute allograft rejection. TGF-β/Smad3 signaling is a key pathway in regulating T cell development. We report here that Smad3 is a key transcriptional factor of TGF-β signaling that differentially regulates T cell immune responses in a mouse model of cardiac allograft rejection in which donor hearts from BALB/c mice were transplanted into Smad3 knockout (KO) and wild type (WT) mice. Results showed that the cardiac allograft survival was prolonged in Smad3 KO recipients. This allograft protection was associated with a significant inhibition of proinflammatory cytokines (IL-1β, TNF-α, and MCP-1) and infiltration of neutrophils, CD3+ T cells, and F4/80+ macrophages. Importantly, deletion of Smad3 markedly suppressed T-bet and IFN-γ while enhancing GATA3 and IL-4 expression, resulting in a shift from the Th1 to Th2 immune responses. Furthermore, mice lacking Smad3 were also protected from the Th17-mediated cardiac injury, although the regulatory T cell (Treg) response was also suppressed. In conclusion, Smad3 is an immune regulator in T cell-mediated cardiac allograft rejection. Loss of Smad3 results in a shift from Th1 to Th2 but suppressing Th17 immune responses. Thus, modulation of TGF-β/Smad3 signaling may be a novel therapy for acute allograft rejection.
Highlights
Organ transplantation is the final definitive treatment for the end stage of many organ diseases
The present study demonstrated that mice lacking Smad3 developed less severe allograft rejection and improved the allograft survival rate in cardiac transplantation
Results from this study suggested that Smad3 is an important regulator of T cell immunity and differentially regulates the T cell immune response during acute cardiac transplantation rejection
Summary
Organ transplantation is the final definitive treatment for the end stage of many organ diseases. Allograft rejection remains the main impediment in organ transplantation clinically. CD4+ T helper (Th) cells play a critical role in transplant rejection, especially in acute allograft rejection [1]. This is supported by the finding that adoptive transfer of CD4+ T cells promotes but depletion of this T cell population inhibits allograft rejection [2, 3]. It is clear that naive CD4+ T cells can proliferate and differentiate into. Recent studies indicated that transforming growth factor-β (TGF-β) is a master regulator in T cell development, homeostasis, tolerance, and differentiation during the immune response [4]. Binding of TGF-β1 to its receptor II (TβRII) can activate the TGF-β receptor type I (TβRI)-kinase, resulting in the phosphorylation of Smad and Smad, two receptor-associated Smads
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