Donor lymphocyte infusion induces long-term donor-specific cardiac xenograft survival through activation of recipient double-negative regulatory T cells
Donor lymphocyte infusion induces long-term donor-specific cardiac xenograft survival through activation of recipient double-negative regulatory T cells
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DOI：
10.4049/jimmunol.175.5.3409
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发表时间：
2005-09-01
影响因子：
4.4
通讯作者：
Zhang, L
中科院分区：
文献类型：
--
作者：
Chen, WH;Zhou, DJ;Zhang, L
先前的研究表明，移植前供体淋巴细胞输注（DLI）可以提高异种移植物的存活率。然而，DLI诱导异种移植物存活的机制仍然不清楚。使用T细胞亚群缺陷小鼠作为受体，我们发现CD4(+)，而不是CD8(+)， T细胞是介导一致性异种心脏移植排斥所必需的。CD4(+) T细胞过继转移诱导CD4（-/-）小鼠对接受的异种心脏移植物产生排斥反应。这种排斥反应可以在没有任何其他治疗的情况下通过移植前DLI来预防。此外，我们证明了DLI激活α - β - tcr (+)CD3(+)CD4(+)CD8（+）双阴性（DN）调节性T （Treg）细胞，并且DLI激活的DN Treg细胞可以在体外抑制供体特异性异种反应性CD4(+) T细胞的增殖。更重要的是，来自异种移植受体的dli活化的DN Treg细胞的过继转移可以抑制异种反应性CD4(+) T细胞的增殖及其在体内产生IL-2和ifn - γ的能力。dli活化的DN Treg细胞过继性转移也能以ag特异性的方式阻止CD4(+) T细胞介导的异种心脏移植排斥反应。这些数据提供了直接证据，证明DLI可以激活受体DN Treg细胞，通过抑制体内供体特异性CD4(+) T细胞的增殖和功能，诱导供体特异性心脏移植长期存活。
Previous studies have shown that pretransplant donor lymphocyte infusion (DLI) can enhance xenograft survival. However, the mechanism by which DLI induces xenograft survival remains obscure. Using T cell subset-deficient mice as recipients we show that CD4(+), but not CD8(+), T cells are necessary to mediate the rejection of concordant cardiac xenografts. Adoptive transfer of naive CD4(+) T cells induces rejection of accepted cardiac xenografts in CD4(-/-) mice. This rejection can be prevented by pretransplant DLI in the absence of any other treatment. Furthermore, we demonstrate that DLI activates alpha beta-TCR(+)CD3(+)CD4(+)CD8(+) double-negative (DN) regulatory T (Treg) cells in xenograft recipients, and that DLI-activated DN Treg cells can inhibit the proliferation of donor-specific xenoreactive CD4(+) T cells in vitro. More importantly, adoptive transfer of DLI-activated DN Treg cells from xenograft recipients can suppress the proliferation of xenoreactive CD4(+) T cells and their ability to produce IL-2 and IFN-gamma in vivo. Adoptive transfer of DLI-activated DN Treg cells also prevents CD4(+) T cell-mediated cardiac xenograft rejection in an Ag-specific fashion. These data provide direct evidence that DLI can activate recipient DN Treg cells, which can induce donor-specific long-term cardiac xenograft survival by suppressing the proliferation and function of donor-specific CD4(+) T cells in vivo.