Zhai Yuan, Meng Lingzhong, Gao Feng, Wang Yue, Busuttil Ronald W, Kupiec-Weglinski Jerzy W
Division of Liver and Pancreas Transplantation, Department of Surgery, The Dumont-University of California Los Angeles (UCLA) Transplant Center, David Geffen School of Medicine, UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
J Immunol. 2006 May 15;176(10):5988-94. doi: 10.4049/jimmunol.176.10.5988.
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.
尽管CD4(+)调节性T细胞（Treg）在移植耐受中的作用已得到证实，但Treg在体内的诱导机制及功能仍不清楚。最近有研究表明，Toll样受体4（TLR4）信号传导参与调节CD4(+)CD25(+) Treg的功能。在本研究中，我们首先在小鼠心脏移植模型中研究了受体TLR4在CD154阻断后获得可操作性CD4(+) Treg过程中的作用。然后，我们确定同种异体移植耐受受体中TLR4的激活是否会逆转由CD4(+) Treg介导的同种异体免疫抑制。我们发现，与野生型受体相似，单剂量抗CD154单克隆抗体可在TLR4缺陷受体中轻易诱导出供体特异性免疫耐受。通过一系列清除实验，检测野生型和TLR4基因敲除长期宿主中CD4(+) Treg抑制二次供体型试验皮肤移植排斥反应及体内抑制同种异体反应性CD8(+) T细胞激活的能力，证实了CD4(+) Treg在两种宿主中的功能和表型。此外，在耐受受体中，外源性脂多糖（LPS）输注联合供体型皮肤移植攻击后激活TLR4，未能打破Treg介导的免疫抑制。总之，我们的数据揭示了同种异体移植耐受受体中CD4(+) Treg的一个独特特性，即其诱导和功能独立于TLR4信号传导。
