Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells.
Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells.
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DOI：
10.4049/jimmunol.0804253
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Ostrand-Rosenberg S
中科院分区：
文献类型：
--
作者：
Hanson EM;Clements VK;Sinha P;Ilkovitch D;Ostrand-Rosenberg S
有效的细胞介导的抗肿瘤免疫需要肿瘤反应性T细胞的活化和活化的T细胞向肿瘤部位的运输。这些过程涉及淋巴细胞从血液和体液中外渗，以及它们归巢到淋巴结和肿瘤。L-选择素（CD 62 L）是这些过程中的重要分子。它将幼稚淋巴细胞导向外周淋巴结，在那里它们被激活，并将幼稚淋巴细胞运输到炎症环境，如肿瘤。患有晚期癌症的个体由于髓源性抑制细胞（MDSC）而受到免疫抑制，所述髓源性抑制细胞（MDSC）是一群未成熟的髓细胞，其响应于肿瘤分泌的促炎因子而积累至高水平。我们现在证明，在癌症患者中常见的L-选择素T细胞水平的降低与MDSC水平呈负相关。三条证据表明MDSC直接下调幼稚T细胞上的L-选择素：1）与肿瘤诱导的MDSC共培养的幼稚T细胞具有降低的L-选择素; 2）具有升高的MDSC水平的无肿瘤老年小鼠中的T细胞具有降低的L-选择素，和3）用纤溶酶原激活剂尿激酶处理以升高MDSC的无肿瘤小鼠的腹膜渗出物T细胞具有降低的L-选择素水平。MDSC可能通过ADAM 17（一种去整合素和金属蛋白酶结构域17）的质膜表达来下调L-选择素，ADAM 17是一种切割L-选择素胞外域的酶。因此，MDSC下调幼稚T细胞上的L-选择素水平，降低它们归巢到它们将被激活的位点的能力。这是MDSC抑制抗肿瘤免疫的另一种机制。
Effective cell-mediated antitumor immunity requires the activation of tumor-reactive T cells and the trafficking of activated T cells to tumor sites. These processes involve the extravasation of lymphocytes from the blood and lymphatics, and their homing to lymph nodes and tumors. L-selectin (CD62L) is an important molecule in these processes. It directs naive lymphocytes to peripheral lymph nodes where they become activated and it traffics naive lymphocytes to inflammatory environments, such as tumors. Individuals with advanced cancer are immune suppressed due to myeloid-derived suppressor cells (MDSC), a population of immature myeloid cells that accumulate to high levels in response to tumor-secreted and proinflammatory factors. We now demonstrate that the reduction in T cell levels of L-selectin that is commonly seen in individuals with cancer inversely correlates with MDSC levels. Three lines of evidence demonstrate that MDSC directly down-regulate L-selectin on naive T cells: 1) naive T cells cocultured with tumor-induced MDSC have reduced L-selectin; 2) T cells in tumor-free aged mice with elevated levels of MDSC have reduced L-selectin, and 3) peritoneal exudate T cells of tumor-free mice treated with plasminogen activator urokinase to elevate MDSC have reduced levels of L-selectin. MDSC are likely to down-regulate L-selectin through their plasma membrane expression of ADAM17 (a disintegrin and metalloproteinase domain 17), an enzyme that cleaves the ectodomain of L-selectin. Therefore, MDSC down-regulate L-selectin levels on naive T cells, decreasing their ability to home to sites where they would be activated. This is another mechanism by which MDSC inhibit antitumor immunity.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
64.8
作者：
GALLATIN, WM;WEISSMAN, IL;BUTCHER, EC
通讯作者：
BUTCHER, EC
影响因子：
4.4
作者：
Almand, B;Clark, JI;Gabrilovich, DI
通讯作者：
Gabrilovich, DI
影响因子：
11.2
作者：
Ilkovitch, Dan;Handel-Fernandez, Mary Ellen;Lopez, Diana M.
通讯作者：
Lopez, Diana M.
影响因子：
4.8
作者：
Arribas, J;Coodly, L;Massague, J
通讯作者：
Massague, J