Gong J, Apostolopoulos V, Chen D, Chen H, Koido S, Gendler S J, McKenzie I F, Kufe D
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, Austin Research Institute, Heidelberg, Victoria, Australia.
Immunology. 2000 Nov;101(3):316-24. doi: 10.1046/j.1365-2567.2000.00101.x.
Mice transgenic for the human MUC1 carcinoma-associated antigen (MUC1.Tg) are tolerant to immunization with MUC1 antigen. Recent studies, however, have demonstrated that immunization of MUC1.Tg mice with fusions of MUC1-positive tumour and dendritic cells (FC/MUC1) reverses MUC1 unresponsiveness and results in rejection of established MUC1-positive pulmonary metastases. Here we demonstrate that lymph node cells from MUC1.Tg mice immunized with the FC/MUC1 fusion cells proliferate in response to MUC1 antigen by a mechanism dependent on the function of CD4, major histocompatibility complex (MHC) class II, B7-1, B7-2, CD28, CD40 and CD40 ligand. The findings demonstrate that stimulation of lymph node cells with MUC1 results in selection of MUC1-specific CD8+ T cells. We show that the CD8+ T cells exhibit MUC1-specific cytotoxic T lymphocyte (CTL) activity by recognition of MUC1 peptides presented in the context of MHC class I molecules Kb and Db. The MUC1-specific CD8+ T cells also exhibit antitumour activity against MUC1-positive metastases, but with no apparent reactivity against normal tissues. These results indicate that immunization of MUC1.Tg mice with FC/MUC1 reverses immunological unresponsiveness to MUC1 by presentation of MUC1 peptides in the presence of costimulatory signals and generates MHC-restricted MUC1-specific CD8+ T cells.
转染人MUC1癌相关抗原的转基因小鼠（MUC1.Tg）对MUC1抗原免疫耐受。然而，最近的研究表明，用MUC1阳性肿瘤与树突状细胞的融合物（FC/MUC1）免疫MUC1.Tg小鼠可逆转对MUC1的无反应性，并导致已形成的MUC1阳性肺转移灶被排斥。在此，我们证明，用FC/MUC1融合细胞免疫的MUC1.Tg小鼠的淋巴结细胞通过依赖于CD4、主要组织相容性复合体（MHC）II类、B7-1、B7-2、CD28、CD40和CD40配体功能的机制，对MUC1抗原产生增殖反应。这些发现表明，用MUC1刺激淋巴结细胞可导致选择MUC1特异性CD8+T细胞。我们显示，CD8+T细胞通过识别在MHC I类分子Kb和Db背景下呈递的MUC1肽，表现出MUC1特异性细胞毒性T淋巴细胞（CTL）活性。MUC1特异性CD8+T细胞也表现出对MUC1阳性转移灶的抗肿瘤活性，但对正常组织无明显反应性。这些结果表明，用FC/MUC1免疫MUC1.Tg小鼠通过在共刺激信号存在的情况下呈递MUC1肽，逆转对MUC1的免疫无反应性，并产生MHC限制性MUC1特异性CD8+T细胞。
