Impaired tumor rejection by memory CD8 T cells in mice with NKG2D dysfunction
Impaired tumor rejection by memory CD8 T cells in mice with NKG2D dysfunction
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DOI：
10.1002/ijc.26191
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发表时间：
2012-10-01
影响因子：
6.4
通讯作者：
Steinle, Alexander
中科院分区：
文献类型：
--
作者：
Andre, Maya Caroline;Sigurdardottir, Dagmar;Steinle, Alexander
细胞毒性T细胞是强大的抗肿瘤免疫反应的重要效应器。然而，肿瘤浸润性CD8 T细胞往往功能受损。CD8 T细胞抗肿瘤活性不足可能是由于缺乏共刺激信号。NKG2D是CD8 T细胞上的共刺激受体，促进应激细胞和恶性细胞的免疫识别，促进NK和CD8 T细胞的肿瘤排斥反应，并有助于自发恶性肿瘤的免疫监视。先前的报道表明NKG2D参与建立CD8 T细胞介导的抗肿瘤记忆。然而，NKG2D在记忆性CD8 T细胞反应的产生和效应期的意义在很大程度上是未知的。为了解决这些问题，我们使用了一种转基因小鼠模型（H2-Kb-MICA小鼠），其中人类NKG2D配体MICA无处不在且组成性表达，导致NKG2D严重功能障碍。卵清蛋白（OVA）特异性（H2-Kb/OVA257264）记忆性CD8 T细胞来自内源性T细胞池和过继转移的OVA特异性T- i记忆细胞都不能控制H2-Kb- mica小鼠中表达OVA的淋巴瘤的生长。虽然这些小鼠在抗原刺激下记忆T细胞的扩增与对照组没有什么不同，但H2-Kb-MICA小鼠的CD8记忆T细胞在体内并没有有效地消除肿瘤细胞。总之，我们的数据表明，NKG2D在记忆性CD8 T细胞的产生和扩增中没有主要作用，而是大大增强了重新激活的记忆性T细胞的细胞溶解效应反应，从而有助于有效的肿瘤排斥。
Cytotoxic T cells are important effectors for robust antitumor immune responses. However, tumor-infiltrating CD8 T cells are often functionally impaired. Insufficient antitumor activity of CD8 T cells can be due to a lack of costimulatory signals. NKG2D is such a costimulatory receptor on CD8 T cells that facilitates immunorecognition of stressed and malignant cells, promotes tumor rejection by NK and CD8 T cells and contributes to immunosurveillance of spontaneous malignancies. Previous reports suggested an involvement of NKG2D in establishing CD8 T cell-mediated antitumor memory. However, the significance of NKG2D for the generation and effector phase of memory CD8 T cell responses is largely unknown. To address these issues, we made use of a transgenic mouse model (H2-Kb-MICA mice) where the human NKG2D ligand MICA is ubiquitously and constitutively expressed resulting in a severe dysfunction of NKG2D. Both, ovalbumin (OVA)-specific (H2-Kb/OVA257264) memory CD8 T cells arisen from the endogenous T cell pool and adoptively transferred OVA-specific OT-I memory cells were unable to control growth of an OVA-expressing lymphoma in H2-Kb-MICA mice. While expansion of memory T cells in these mice on antigen challenge was not different from controls, CD8 memory T cells of H2-Kb-MICA mice did not effectively eliminate tumor cells in vivo. Altogether, our data suggest that NKG2D has no major role in the generation and expansion of memory CD8 T cells, but rather substantially enhances the cytolytic effector responses of reactivated memory T cells and thereby contributes to an efficacious tumor rejection.