Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion.
Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion.
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淋巴瘤内皮优先表达 Tim-3 并通过介导免疫逃避促进淋巴瘤的进展
DOI：
10.1084/jem.20090397
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发表时间：
2010-03-15
期刊：
影响因子：
--
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Huang X;Bai X;Cao Y;Wu J;Huang M;Tang D;Tao S;Zhu T;Liu Y;Yang Y;Zhou X;Zhao Y;Wu M;Wei J;Wang D;Xu G;Wang S;Ma D;Zhou J
血管生成越来越多地被认为是一个重要的与淋巴瘤的进展和新的方式作为一个有吸引力的目标。我们报告了一个以前未认识到的机制，淋巴瘤内皮细胞通过与循环T细胞相互作用促进淋巴瘤的生长和传播，并抑制CD 4 + T细胞的活化。淋巴瘤和反应性淋巴结微切内皮细胞的全球基因表达谱显示，T细胞免疫球蛋白和粘蛋白结构域的分子3（Tim-3）优先表达于淋巴瘤衍生的内皮细胞（EC）。临床上，B细胞淋巴瘤内皮细胞中Tim-3的表达水平与淋巴瘤的播散和预后密切相关。在体外，Tim-3+ ECs通过激活白细胞介素-6-STAT 3途径抑制CD 4 + T淋巴细胞的活化，抑制Th 1极化，并提供保护性免疫，从而调节T细胞对淋巴瘤替代抗原的应答。在淋巴瘤小鼠模型中，表达Tim-3的EC通过抑制CD 4 + T细胞的激活和Th 1极化来促进淋巴瘤的发生、生长和扩散。我们的研究结果有力地表明，淋巴瘤内皮细胞不仅是一个血管系统，而且是一个功能屏障，促进淋巴瘤免疫耐受的建立。这些发现强调了一种新的分子机制，该机制是增强肿瘤免疫治疗效果和控制转移性疾病的潜在靶点。
Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4+ T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3+ ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4+ T lymphocytes through the activation of the interleukin-6–STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3–expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4+ T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.
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