Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8+ T cells
Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8+ T cells
复制标题
DOI：
10.4049/jimmunol.179.2.845
复制
发表时间：
2007-07-15
影响因子：
4.4
通讯作者：
Walker, Paul R.
中科院分区：
文献类型：
--
作者：
Masson, Frederick;Calzascia, Thomas;Walker, Paul R.
在抗肿瘤免疫应答的引发阶段，CD 8（+）T细胞经历由次级淋巴器官中的专职APC驱动的分化程序。这导致克隆扩增和获得效应子功能和特异性粘附分子模式。这个程序是否可以在效应器阶段重新塑造，以适应效应器部位的微环境是未知的。我们在小鼠脑肿瘤模型中使用肿瘤特异性CD 8（+）T细胞的过继转移以及恶性胶质瘤患者的自发免疫应答研究了这一点。我们的数据显示，银经验丰富的肿瘤特异性T细胞在脑实质内的增殖。此外，CD 8（+）T细胞在脑中进一步分化，表现出增强的IFN-γ和颗粒酶B表达以及α（E）（CD 103）β（7）整联蛋白的诱导。这种意想不到的整合素表达鉴定了由脑微环境调节的CD 8（+）T细胞亚群，并且还具有功能性后果：表达α（E）（CD 103）β 7的CD 8（+）T细胞在脑中的滞留增强。进一步研究了浸润人恶性胶质瘤的CD 8（+）T细胞的这些发现; CD 8（+）T细胞表达α，（CD 103）97整联蛋白和颗粒酶B，如在鼠模型中一样。总的来说，我们的数据表明，效应位点在塑造肿瘤免疫的效应期中起着积极的作用。在优化未来的区域肿瘤控制免疫疗法时，应考虑局部扩张和功能重编程的潜力。
During the priming phase of an antitumor immune response, CD8(+) T cells undergo a program of differentiation driven by professional APCs in secondary lymphoid organs. This leads to clonal expansion and acquisition both of effector functions and a specific adhesion molecule pattern. Whether this program can be reshaped during the effector phase to adapt to the effector site microenvironment is unknown. We investigated this in murine brain tumor models using adoptive transfer of tumor-specific CD8(+) T cells, and in spontaneous immune responses of patients with malignant glioma. Our data show proliferation of Ag-experienced tumor-specific T cells within the brain parenchyma. Moreover, CD8(+) T cells further differentiated in the brain, exhibiting enhanced IFN-gamma and granzyme B expression and induction of alpha(E)(CD103)beta(7) integrin. This unexpected integrin expression identified a subpopulation of CD8(+) T cells conditioned by the brain microenvironment and also had functional consequences: alpha(E)(CD103)beta 7-expressing CD8(+) T cells had enhanced retention in the brain. These findings were further investigated for CD8(+) T cells infiltrating human malignant glioma; CD8(+) T cells expressed a,(CD103)97 integrin and granzyme B as in the murine models. Overall, our data indicate that the effector site plays an active role in shaping the effector phase of tumor immunity. The potential for local expansion and functional reprogramming should be considered when optimizing future immunotherapies for regional tumor control.