Zhang Qian-Jin, Li Xiao-Lin, Wang David, Huang Xiao-Cong, Mathis J Michael, Duan Wei-Ming, Knight David, Shi Runhua, Glass Jonathan, Zhang Dong-Qing, Eisenbach Lea, Jefferies Wilfred A
Department of Cellular Biology and Anatomy, Gene Therapy Program, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
PLoS One. 2008 Aug 29;3(8):e3097. doi: 10.1371/journal.pone.0003097.
The transporter associated with antigen processing (TAP) and the major histocompatibility complex class I (MHC-I), two important components of the MHC-I antigen presentation pathway, are often deficient in tumor cells. The restoration of their expression has been shown to restore the antigenicity and immunogenicity of tumor cells. However, it is unclear whether TAP and MHC-I expression in tumor cells can affect the induction phase of the T cell response. To address this issue, we expressed viral antigens in tumors that are either deficient or proficient in TAP and MHC-I expression. The relative efficiency of direct immunization or immunization through cross-presentation in promoting adaptive T cell responses was compared. The results demonstrated that stimulation of animals with TAP and MHC-I proficient tumor cells generated antigen specific T cells with greater killing activities than those of TAP and MHC-I deficient tumor cells. This discrepancy was traced to differences in the ability of dendritic cells (DCs) to access and sample different antigen reservoirs in TAP and MHC-I proficient versus deficient cells and thereby stimulate adaptive immune responses through the process of cross-presentation. In addition, our data suggest that the increased activity of T cells is caused by the enhanced DC uptake and utilization of MHC-I/peptide complexes from the proficient cells as an additional source of processed antigen. Furthermore, we demonstrate that immune-escape and metastasis are promoted in the absence of this DC 'arming' mechanism. Physiologically, this novel form of DC antigen sampling resembles trogocytosis, and acts to enhance T cell priming and increase the efficacy of adaptive immune responses against tumors and infectious pathogens.
与抗原加工相关的转运体（TAP）和主要组织相容性复合体I类（MHC-I）是MHC-I抗原呈递途径的两个重要组成部分，在肿瘤细胞中常常缺失。已表明恢复它们的表达可恢复肿瘤细胞的抗原性和免疫原性。然而，尚不清楚肿瘤细胞中TAP和MHC-I的表达是否会影响T细胞反应的诱导阶段。为了解决这个问题，我们在TAP和MHC-I表达缺陷或正常的肿瘤中表达病毒抗原。比较了直接免疫或通过交叉呈递免疫在促进适应性T细胞反应中的相对效率。结果表明，用TAP和MHC-I正常的肿瘤细胞刺激动物产生的抗原特异性T细胞比TAP和MHC-I缺陷的肿瘤细胞具有更强的杀伤活性。这种差异可追溯到树突状细胞（DC）在TAP和MHC-I正常与缺陷细胞中获取和采样不同抗原库的能力差异，从而通过交叉呈递过程刺激适应性免疫反应。此外，我们的数据表明，T细胞活性的增加是由于DC从正常细胞中摄取和利用MHC-I/肽复合物作为加工抗原的额外来源增强所致。此外，我们证明在没有这种DC“武装”机制的情况下会促进免疫逃逸和转移。从生理上讲，这种新型的DC抗原采样类似于胞啃作用，作用是增强T细胞启动并提高针对肿瘤和传染性病原体的适应性免疫反应的效力。
