Mahnke Yolanda D, Schwendemann Jochen, Beckhove Philipp, Schirrmacher Volker
Division of Cellular Immunology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
Immunology. 2005 Jul;115(3):325-36. doi: 10.1111/j.1365-2567.2005.02163.x.
LacZ (Gal)-reactive immune cells were transferred into athymic nu/nu mice inoculated with Gal-expressing syngeneic tumour cells (ESbL-Gal) in order to study tumour-protective T-cell memory. This transfer prevented tumour outgrowth in recipients and resulted in the persistence of a high frequency of Gal-specific CD8(+) T cells in the bone marrow and spleen. In contrast, such Ag-specific memory CD8(+) T cells were not detectable by peptide-major histocompatibility complex (MHC) multimer staining in animals that had not previously received an antigenic challenge. Even though CD44(hi) memory T cells from the bone marrow showed a significantly higher turnover rate, as judged by bromodeoxyuridine (BrdU) incorporation, than respective cells from spleen or lymph nodes, as well as in comparison to CD44(lo) naïve T cells, these findings suggest that tumour-associated antigen (TAA) from residual dormant tumour cells are implicated in maintaining high frequencies of long-term surviving Gal-specific memory CD8(+) T cells. Memory T cells could be recruited to the peritoneal cavity by tumour vaccination of immunoprotected nu/nu mice and exhibited ex vivo antitumour reactivity. Long-term immune memory and tumour protection could be maintained over four successive transfers between tumour-inoculated recipients, which involved periodic antigenic restimulation in vivo prior to reisolating the cells for adoptive transfer. Using a cell line (ESbL-Gal-BM) that was established from dormant tumour cells isolated from the bone marrow of immunoprotected animals, it could be demonstrated that the tumour cells had up-regulated the expression of MHC class I molecules and down-regulated the expression of several adhesion molecules during the in vivo passage. Our results suggest that the bone marrow microenvironment has special features that are of importance for the maintenance of tumour dormancy and immunological T-cell memory, and that a low level of persisting antigen favours the maintenance of Ag-specific memory T cells over irrelevant memory T cells.
为了研究肿瘤保护性T细胞记忆，将LacZ（半乳糖）反应性免疫细胞转移到接种了表达半乳糖的同基因肿瘤细胞（ESbL-半乳糖）的无胸腺裸鼠体内。这种转移阻止了受体小鼠体内肿瘤的生长，并导致骨髓和脾脏中高频率的半乳糖特异性CD8(+) T细胞持续存在。相比之下，在先前未接受抗原刺激的动物中，通过肽-主要组织相容性复合体（MHC）多聚体染色无法检测到此类抗原特异性记忆CD8(+) T细胞。尽管通过溴脱氧尿苷（BrdU）掺入判断，骨髓中的CD44(hi)记忆T细胞的周转率明显高于脾脏或淋巴结中的相应细胞，也高于CD44(lo)幼稚T细胞，但这些发现表明，来自残留休眠肿瘤细胞的肿瘤相关抗原（TAA）与维持高频率的长期存活的半乳糖特异性记忆CD8(+) T细胞有关。通过对免疫保护的裸鼠进行肿瘤疫苗接种，记忆T细胞可以被招募到腹腔，并表现出体外抗肿瘤反应性。在接种肿瘤的受体之间进行连续四次转移时，可以维持长期免疫记忆和肿瘤保护，这包括在重新分离细胞进行过继转移之前，在体内进行定期抗原再刺激。使用从免疫保护动物骨髓中分离的休眠肿瘤细胞建立的细胞系（ESbL-半乳糖-BM），可以证明肿瘤细胞在体内传代过程中上调了MHC I类分子的表达，并下调了几种粘附分子的表达。我们的结果表明，骨髓微环境具有特殊特征，对维持肿瘤休眠和免疫T细胞记忆很重要，并且低水平的持续抗原有利于维持抗原特异性记忆T细胞而非无关记忆T细胞。
