Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-Cell activity to suppress alloimmune responses
Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-Cell activity to suppress alloimmune responses
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DOI：
10.1097/01.tp.0000256293.90270.e8
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发表时间：
2007-03-27
期刊：
影响因子：
6.2
通讯作者：
Li, Xiao-Kang
中科院分区：
文献类型：
--
作者：
Kitazawa, Yusuke;Fujino, Masayuki;Li, Xiao-Kang
背景免疫调节性CD 4 + CD 25 + T（调节性T; Treg）细胞在诱导和维持自身耐受中起着至关重要的作用。它们对于T细胞的稳态、自身免疫的预防和对同种异体供体移植物的耐受的诱导是必不可少的。然而，其功能的基本机制仍然大多难以捉摸。因此，我们在此研究了Treg细胞通过程序性死亡（PD）-1/PD-1配体（PD-L1）途径在其对同种异体抗原的应答中的关键作用。采用体外混合淋巴细胞反应（MLR）、移植物抗宿主病（GvHD）和皮肤移植模型研究PD-1/PD-L1通路的作用机制。使用抗PD-L1单克隆抗体（mAb）阻断PD-1/PD-L1通路可抑制Treg细胞抑制和恢复体外CD 4 + CD 25-T细胞增殖的能力。将同种异体C57 BL/6（H-2K（B））脾细胞过继转移至NOD/SCID（H-2K（d））小鼠后，GvHD是致死的，除非还包括CD 25 + T细胞。引人注目的是，CD 25+细胞对GvHD的抑制被抗PD-L1 mAb给药消除。Treg细胞介导的抑制的消除也可以在BalB/c（H-2K（d））至B6/Rag-2KO（H-2k（B）皮肤移植模型中证明。PD-1/PD-L1通路的阻断消除了Treg介导的免疫调节，因此表明PD-1/PD-L1通路是Treg抑制CD 4 + CD 25-T细胞的同种异体反应性应答所必需的。这一发现对于阐明同种异体移植排斥反应和GvHD的机制具有重要意义。
Background. Immune regulatory CD4+CD25+ T (regulatory T; Treg) cells play a vital role in the induction and maintenance of self-tolerance. They are essential for the homeostasis of T cells, the prevention of autoimmunity, and the induction of tolerance to allogeneic donor grafts. However, the underlying mechanism of their functions remains mostly elusive. Therefore, we investigated here a crucial role of Treg cells in their response to alloantigen via the programmed death (PD)-1/PD-1 ligand (PD-L1) pathway.Methods. In vitro mixed lymphocyte reaction (MLR) assay, graft-versus-host disease (GvHD) and a skin transplantation model were used to evaluate the mechanisms of PD-1/PD-L1 pathway.Results. Blockade ofthePD-1/PD-L1 pathway using anti-PD-L1 monoclonal antibodies (mAb) is found to inhibit Treg cell's ability to suppress and restore CD4 + CD25-T-cell proliferation in vitro. GvHD was lethal after adoptive transfer of allogeneic C57BL/6 (H-2K(b)) spleen cells to NOD/SCID (H-2K(d)) mice unless CD25+ T cells were also included. Strikingly, the suppression of GvHD by CD25+ cells was abrogated by anti-PD-L1 mAb administration. The abrogation of Treg-cell-mediated suppression could also be demonstrated in a Balb/c (H-2K(d)) to B6/Rag-2KO (H-2k(b) skin-aflograft model.Conclusions. The blockade of the PD-1/PD-L1 pathway abrogates Treg-mediated immunoregulation, thus suggesting that the PD-1/PD-L1 pathway is required for Treg suppression of the alloreactive responses of CD4+CD25-T cells. This finding has important implications for clarifying the mechanisms of allograft rejection and GvHD.