Liver sinusoidal endothelial cells tolerize T cells across MHC barriers in mice
Liver sinusoidal endothelial cells tolerize T cells across MHC barriers in mice
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DOI：
10.4049/jimmunol.175.1.139
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发表时间：
2005-07-01
影响因子：
4.4
通讯作者：
Asahara, T
中科院分区：
文献类型：
--
作者：
Onoe, T;Ohdan, H;Asahara, T
尽管小鼠肝脏跨越MHC屏障移植通常在没有受体免疫抑制的情况下被接受，但其潜在机制仍有待澄清。为了鉴定有助于诱导这种耐受状态的细胞类型，我们建立了混合肝成分细胞-淋巴细胞反应（MIBR）测定。将辐照的C57 BL/6（B6）或BALB/c小鼠肝组成细胞（HC）和CFSE标记的B6脾细胞共培养。在同种异体Mc中，完整的HC不促进T细胞增殖。当肝窦内皮细胞（LSEC）从HC刺激物中耗尽时，同种异体MCLs导致反应性CD 4（+）和CD 8（+）T细胞显著增殖。为了测试LSEC对同种异体反应性T细胞的耐受能力，用辐照的BALB/c脾细胞再刺激已经穿过B6、BALB/c或SJL/j LSEC单层的B6脾细胞。再刺激后，观察到通过同种异体BALB/c LSEC迁移的T细胞无反应性，以及通过同基因B6或第三方SJL/j LSEC迁移的T细胞显著增殖。Fas配体缺陷的BALB/c LSEC的跨膜迁移不能使CD 4（+）T细胞耐受。因此，我们证明，在幼稚LSEC上表达的Fas配体可以通过直接途径在同种抗原识别后赋予致耐受性潜力。这为肝移植耐受提供了一种新的相关机制。总之，LSEC能够调节具有直接同种特异性的多克隆T细胞群体，并且Fas/Fas配体途径参与这种LSEC介导的T细胞调节。
Although livers transplanted across MHC barriers in mice are normally accepted without recipient immune suppression, the underlying mechanisms remain to be clarified. To identify the cell type that contributes to induction of such a tolerance state, we established a mixed hepatic constituent cell-lymphocyte reaction (MHLR) assay. Irradiated C57BL/6 (B6) or BALB/c mouse hepatic constituent cells (HCs) and CFSE-labeled B6 splenocytes were cocultured. In allogeneic MHLR, whole HCs did not promote T cell proliferation. When liver sinusoidal endothelial cells (LSECs) were depleted from HC stimulators, allogeneic MHLR resulted in marked proliferation of reactive CD4(+) and CD8(+) T cells. To test the tolerizing capacity of the LSECs toward alloreactive T cells, B6 splenocytes that had transmigrated through monolayers of B6, BALB/c, or SJL/j LSECs were restimulated with irradiated BALB/c splenocytes. Nonresponsiveness of T cells that had transmigrated through allogeneic BALB/c LSECs and marked proliferation of T cells transmigrated through syngeneic B6 or third-party SJL/j LSECs were observed after the restimulation. Transmigration across the Fas ligand-deficient BALB/c LSECs failed to render CD4(+) T cells tolerant. Thus, we demonstrate that Fas ligand expressed on naive LSECs can impart tolerogenic potential upon alloantigen recognition via the direct pathway. This presents a novel relevant mechanism of liver allograft tolerance. In conclusion, LSECs are capable of regulating a polyclonal population of T cells with direct allospecificity, and the Fas/Fas ligand pathway is involved in such LSEC-mediated T cell regulation.