Gamma-IFN-inducible-lysosomal thiol reductase modulates acidic proteases and HLA class II antigen processing in melanoma
Gamma-IFN-inducible-lysosomal thiol reductase modulates acidic proteases and HLA class II antigen processing in melanoma
复制标题
DOI：
10.1007/s00262-008-0483-8
复制
发表时间：
2008-10-01
影响因子：
5.8
通讯作者：
Haque, Azizul
中科院分区：
文献类型：
--
作者：
Goldstein, Oliver G.;Hajiaghamohseni, Laela M.;Haque, Azizul
HLA II类限制性抗原（Ag）加工和呈递对于CD 4 + T细胞的活化是重要的，所述CD 4 + T细胞是免疫应答的中央协调细胞。大多数黑素瘤细胞表达或可被诱导表达HLA II类蛋白。因此，它们是II类限制性CD 4 + T细胞免疫介导消除的主要靶标。我们以前已经表明，人类黑色素瘤细胞缺乏一种重要的酶，γ干扰素诱导的溶酶体硫醇还原酶（GILT），能够扰乱这些肿瘤的免疫识别。在这里，我们表明，GILT在人类黑色素瘤细胞中的表达增强了银加工和介绍通过HLA II类分子。我们还表明，GILT的表达影响黑色素瘤细胞中的半胱氨酸蛋白酶，组织蛋白酶B，L和S，以及一个乙酰基蛋白酶组织蛋白酶D的活性形式的产生。机制研究表明，GILT不调节酸性组织蛋白酶在转录水平上，而是它与组织蛋白酶共定位和影响HLA II类抗原处理。黑色素瘤细胞中的GILT表达也升高了HLA-DM分子，其有利于表位加载到内溶酶体隔室中的II类上，从而增强CD 4 + T细胞识别。这些数据表明，GILT表达黑色素瘤细胞可以证明是非常有前途的直接抗原呈递和CD 4 + T细胞识别，并可能有直接的影响癌症疫苗的设计。
HLA class II-restricted antigen (Ag) processing and presentation are important for the activation of CD4+ T cells, which are the central orchestrating cells of immune responses. The majority of melanoma cells either expresses, or can be induced to express, HLA class II proteins. Thus, they are prime targets for immune mediated elimination by class II-restricted CD4+ T cells. We have previously shown that human melanoma cells lack an important enzyme, gamma interferon-inducible lysosomal thiol-reductase (GILT), capable of perturbing immune recognition of these tumors. Here, we show that GILT expression in human melanoma cells enhances Ag processing and presentation via HLA class II molecules. We also show that GILT expression influences the generation of active forms of cysteinyl proteases, cathepsins B, L and S, as well as an aspartyl protease cathepsin D in melanoma cells. Mechanistic studies revealed that GILT does not regulate acidic cathepsins at the transcriptional level; rather it colocalizes with the cathepsins and influences HLA class II Ag processing. GILT expression in melanoma cells also elevated HLA-DM molecules, which favor epitope loading onto class II in the endolysosomal compartments, enhancing CD4+ T cell recognition. These data suggest that GILT-expressing melanoma cells could prove to be very promising for direct antigen presentation and CD4+ T cell recognition, and may have direct implications for the design of cancer vaccines.