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Yuan Zhai, Lingzhong Meng, Feng Gao, Yue Wang, Ronald W Busuttil, Jerzy W Kupiec-Weglinski, CD4+ T Regulatory Cell Induction and Function in Transplant Recipients after CD154 Blockade Is TLR4 Independent, The Journal of Immunology, Volume 176, Issue 10, May 2006, Pages 5988–5994, https://doi.org/10.4049/jimmunol.176.10.5988
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Abstract
Although the role of CD4+ T regulatory cells (Treg) in transplantation tolerance has been established, putative mechanisms of Treg induction and function in vivo remain unclear. TLR4 signaling has been implicated in the regulation of CD4+CD25+ Treg functions recently. In this study, we first examined the role of recipient TLR4 in the acquisition of operational CD4+ Treg following CD154 blockade in a murine cardiac transplant model. Then, we determined whether TLR4 activation in allograft tolerant recipients would reverse alloimmune suppression mediated by CD4+ Treg. We document that donor-specific immune tolerance was readily induced in TLR4-deficient recipients by a single dose of anti-CD154 mAb, similar to wild-type counterparts. The function and phenotype of CD4+ Treg in both wild-type and TLR4 knockout long-term hosts was demonstrated by a series of depletion experiments examining their ability to suppress the rejection of secondary donor-type test skin grafts and to inhibit alloreactive CD8+ T cell activation in vivo. Furthermore, TLR4 activation in tolerant recipients following exogenous LPS infusion in conjunction with donor-type skin graft challenge, failed to break Treg-mediated immune suppression. In conclusion, our data reveals a distinctive property of CD4+ Treg in tolerant allograft recipients, whose induction and function are independent of TLR4 signaling.
