Tumor-specific CD4+ T cells are activated by "cross-dressed" dendritic cells presenting peptide-MHC class II complexes acquired from cell-based cancer vaccines
Tumor-specific CD4+ T cells are activated by "cross-dressed" dendritic cells presenting peptide-MHC class II complexes acquired from cell-based cancer vaccines
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DOI：
10.4049/jimmunol.176.3.1447
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发表时间：
2006-02-01
影响因子：
4.4
通讯作者：
Ostrand-Rosenberg, S
中科院分区：
文献类型：
--
作者：
Dolan, BP;Gibbs, KD;Ostrand-Rosenberg, S
固有地表达MHC I类分子并经基因修饰表达MHC II类(MHC II)和共刺激分子的肿瘤细胞具有免疫原性，对同基因小鼠已建立的原发和转移癌具有治疗效果，并激活肿瘤特异性的人类CD4(+)T淋巴细胞。先前的研究表明，这些MHC II疫苗通过在免疫过程中直接激活肿瘤特异性CD4(+)T细胞来增强免疫力。由于树突状细胞(DC)被认为是最有效的APC，我们现在研究了DC在MHC II疫苗激活CD4(+)T细胞中的作用。令人惊讶的是，我们发现DC对于MHC II疫苗的免疫原性是必不可少的；然而，它们通过“变装”来调节其效果。交叉穿戴，或多肽-MHC(PMHC)转移，涉及在疫苗细胞内产生pMHC复合体，并随后将其转移到DC，然后DC将完整的、未处理的复合体呈递给CD4(+)T淋巴细胞。最终结果是，DC是功能性的APC；然而，免疫原性的pMHC复合体是由肿瘤细胞产生的。由于MRC II疫苗细胞不表达MHC II辅助分子不变链和DM，它们可能会将额外的肿瘤抗原表位加载到MHC II分子上，从而激活不同于DC的T细胞。这些数据进一步表明，将细胞材料转移到DC在抗原呈递中是重要的，它们对癌症疫苗的设计有直接的影响。
Tumor cells that constitutively express MHC class I molecules and are genetically modified to express MHC class II (MHC II) and costimulatory molecules are immunogenic and have therapeutic efficacy against established primary and metastatic cancers in syngeneic mice and activate tumor-specific human CD4(+) T lymphocytes. Previous studies have indicated that these MHC II vaccines enhance immunity by directly activating tumor-specific CD4(+) T cells during the immunization process. Because dendritic cells (DCs) are considered to be the most efficient APCs, we have now examined the role of DCs in CD4(+) T cell activation by the MHC II vaccines. Surprisingly, we find that DCs are essential for MHC II vaccine immunogenicity; however, they mediate their effect through "cross-dressing." Cross-dressing, or peptide-MHC (pMHC) transfer, involves the generation of pMHC complexes within the vaccine cells, and their subsequent transfer to DCs, which then present the intact, unprocessed complexes to CD4(+) T lymphocytes. The net result is that DCs are the functional APCs; however, the immunogenic pMHC complexes are generated by the tumor cells. Because MRC II vaccine cells do not express the MHC II accessory molecules invariant chain and DM, they are likely to load additional tumor Ag epitopes onto MHC II molecules and therefore activate a different repertoire of T cells than DCs. These data further the concept that transfer of cellular material to DCs is important in Ag presentation, and they have direct implications for the design of cancer vaccines.