A tumor-associated glycoprotein that blocks MHC class II-dependent antigen presentation by dendritic cells
A tumor-associated glycoprotein that blocks MHC class II-dependent antigen presentation by dendritic cells
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DOI：
10.4049/jimmunol.173.2.1023
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发表时间：
2004-07-15
影响因子：
4.4
通讯作者：
Marks, MS
中科院分区：
文献类型：
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作者：
Gutzmer, R;Li, W;Marks, MS
尽管肿瘤相关抗原(TAA)经常表达，但肿瘤逃避免疫监视。肿瘤细胞通过几种机制逃避CD8(+)T细胞的识别，包括下调MHC I类分子和相关的Ag加工机制。然而，尽管人们普遍认为最佳的抗肿瘤免疫反应需要肿瘤反应性的CD4(+)T细胞，但很少有研究涉及肿瘤细胞如何逃避CD4(+)T细胞的识别。在这项研究中，我们展示了一种常见的TAA，GA733-2，及其小鼠同源基因，小鼠上皮糖蛋白(MEGP)，功能是阻断MHC II类限制的树突状细胞的抗原提呈。GA733-2是一种常见的TAA，在某些上皮组织和树突状细胞亚群中正常低水平表达，但在结肠、乳腺、肺和一些非上皮性肿瘤中高水平表达。我们发现，mEGP或GA733-2在来自小鼠骨髓或人类单核细胞来源的树突状细胞中的异位表达导致剂量依赖性地不能刺激抗原特异性或同种异体反应的CD4(+)T细胞的增殖。树突状细胞暴露在表达mEGP的肿瘤细胞碎片中，也会受到类似的损害。此外，用来自重组腺病毒载体的表达mEGP的树突状细胞免疫的小鼠表现出较弱的抗腺病毒免疫反应。MEGP的抑制作用不是由于功能性MHC-11分子的下调或对T细胞的主动抑制，也不是延伸到T细胞对超抗原的反应。这些结果证明了一种新的机制，肿瘤可以通过表达来逃避CD4(+)T细胞依赖的免疫反应。一个TAA。
Tumors evade immune surveillance despite the frequent expression of tumor-associated Ags (TAA). Tumor cells escape recognition by CD8(+) T cells through several mechanisms, including down-regulation of MHC class I molecules and associated Ag-processing machinery. However, although it is well accepted that optimal anti-tumor immune responses require tumor-reactive CD4(+) T cells, few studies have addressed how tumor cells evade CD4(+) T cell recognition. In this study, we show that a common TAA, GA733-2, and its murine orthologue, mouse epithelial glycoprotein (mEGP), function in blocking MHC class II-restricted Ag presentation by dendritic cells. GA733-2 is a common TAA that is expressed normally at low levels by some epithelial tissues and a subset of dendritic cells, but at high levels on colon, breast, lung, and some nonepithelial tumors. We show that ectopic expression of mEGP or GA733-2, respectively, in dendritic cells derived from:murine bone marrow or human monocytes results in a dose-dependent inability to stimulate proliferation of Ag-specific or alloreactive CD4(+) T cells. Dendritic cells exposed to cell debris from tumors expressing mEGP are similarly compromised. Furthermore, mice immunized with dendritic cells expressing mEGP from a recombinant adenovirus vector exhibited a muted anti-adenovirus immune response. The inhibitory effect of mEGP was not due to down-regulation of functional MHC class 11 molecules or active suppression of T cells, and did not extend to T cell responses to superantigen. These results demonstrate a novel mechanism by which tumors may evade CD4(+) T cell-dependent immune responses through expression. of a TAA.