Differential use of FasL- and perforin-mediated cytolytic mechanisms by T-cell subsets involved in graft-versus-myeloid leukemia responses
Differential use of FasL- and perforin-mediated cytolytic mechanisms by T-cell subsets involved in graft-versus-myeloid leukemia responses
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DOI：
10.1182/blood.v96.3.1047.015k36_1047_1055
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发表时间：
2000-08-01
期刊：
影响因子：
20.3
通讯作者：
Korngold, R
中科院分区：
文献类型：
--
作者：
Hsieh, MH;Korngold, R
在移植物抗白血病（GVL）反应，细胞亚群和效应器机制负责对白血病细胞的细胞毒性在体内仍然很差的特点。先前已经描述了以针对MMB 3.19骨髓性白血病细胞系的CD4（+）和CD8（+）T细胞应答为特征的同基因GVL的鼠模型。MMB3.19表达高水平的功能性Fas和肿瘤坏死因子（TNF）受体，这些受体不抑制促凋亡信号。通过使用穿孔素和Fas配体（FasL）缺陷小鼠，证明了CD4（+）T细胞主要通过使用Fast介导体内抗MMB3.19效应，其次通过穿孔素机制介导抗MMB3.19效应。相反，CD8（+）T细胞主要通过使用穿孔素诱导GVL效应，最低限度地通过Fast机制。虽然CD8（+）T细胞的体内观察反映了其体外细胞毒性T淋巴细胞（CTL）活性，但对于CD4（+）T细胞，体外应答主要由穿孔素途径控制。此外，穿孔素和FasL缺陷小鼠的T细胞裂解MMB3.19靶细胞的能力降低似乎与其细胞毒性功能缺陷直接相关，而不是活化缺陷，因为这些细胞完全能够对肿瘤细胞产生增殖反应。这些发现表明，T细胞亚群的GVL应答可能涉及优先使用不同的细胞毒性机制。特别是，这些发现确定了快速使用的CD4（+）CTL和更新颖的穿孔素使用的CD4（+）T细胞亚群在抗髓性白血病反应中的作用。(C)2000年，美国血液学会。
In graft-versus-leukemia (GVL) responses, the cellular subsets and effector mechanisms responsible for cytotoxicity against leukemic cells in vivo remain poorly characterized. A murine model of syngeneic GVL that features CD4(+) and CD8(+) T-cell responses against the MMB3.19 myeloid leukemia cell line has been previously described. MMB3.19 expresses high levels of functional Fas and tumor necrosis factor (TNF) receptors that do not transduce proapoptotic signals. Through the use of perforin- and Fas ligand (FasL)-deficient mice, it was demonstrated that CD4(+) T cells mediate anti-MMB3.19 effects in vivo primarily through the use of Fast and secondarily through perforin mechanisms. Conversely, CD8(+) T cells induce GVL effects primarily through the use of perforin and minimally through Fast mechanisms. Although the in vivo observations of CD8(+) T cells were reflective of their in vitro cytotoxic T lymphocyte (CTL) activity, for CD4(+) T cells, in vitro responses were dominated by the perforin pathway. In addition, the diminished capacity of T cells from perforin- and FasL-deficient mice to lyse MMB3.19 target cells appeared directly related to their deficient cytotoxic functions rather than to defects in activation because these cells were fully capable of mounting proliferative responses to the tumor cells. These findings demonstrate that GVL responses of T-cell subsets can involve preferential use of different cytotoxic mechanisms. In particular, these findings identify a role for both Fast-employing CD4(+) CTLs and the more novel perforin-utilizing CD4(+) T-cell subset in responses against a myeloid leukemia. (C) 2000 by The American Society of Hematology.