A Color-Coded Reporter Model to Study the Effect of Immunosuppressants on CD8+ T-Cell Memory in Antitumor and Alloimmune Responses
A Color-Coded Reporter Model to Study the Effect of Immunosuppressants on CD8+ T-Cell Memory in Antitumor and Alloimmune Responses
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用于研究免疫抑制剂对抗肿瘤和同种免疫反应中 CD8 T 细胞记忆的影响的颜色编码报告模型
DOI：
10.1097/tp.0b013e318276d358
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Kroemer A
中科院分区：
文献类型：
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作者：
Rovira J;Sabet-Baktach M;Eggenhofer E;Lantow M;Koehl GE;Schlitt HJ;Campistol JM;Geissler EK;Kroemer A
研究背景哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂具有潜在的抗肿瘤特性，可用于减少移植后恶性肿瘤的发生.除了控制肿瘤敏感的增殖和血管生成的影响，mTOR的影响转录因子T-bet和Eomesodermin（Eomes）在CD 8+细胞毒性T细胞（Tc），这是关键在排斥肿瘤，和allografts.MethodsTo研究mTOR在肿瘤和移植免疫中的作用，在抗原特异性的方式，我们使用T细胞受体转基因B6。OTI接受者B6卵蛋白TG供体和OVA-B16 F10黑素瘤细胞。为了追踪与体内抗肿瘤和同种异体免疫相关的颜色编码的OTI-Tc细胞，通过杂交育种表达DsRed的B6来产生CD 8-OTI转基因报告小鼠。含B6的Nagy小鼠。OTI mice.ResultsThe role of mTOR in regulating differentiation and function of alloreactive Tc cells in vitro was explained by stimulating OTI-Tc cells with ovalbumin-transgenic antigen-presenting cells in presence of rapamycin or tacrolimus.雷帕霉素（而非他克莫司）诱导了从CD 62 L-CD 44+效应记忆Tc细胞向CD 62 L + CD 44+中枢记忆Tc细胞的促抗肿瘤表型转变，其特征是T-bet和Eomes水平上调，干扰素-γ和穿孔素水平保持不变。为了进一步的研究，建立了体内模型，其中DsRed+ OTI-Tc细胞过继转移到携带卵清蛋白转基因小鼠皮肤移植物或OVA-B16 F10肿瘤的B6小鼠中，可以通过荧光激活细胞分选分析追踪移植物和肿瘤组织中的效应或记忆Tc细胞。抑制通过独特地调节T-bet和Eomes来避免抗肿瘤记忆Tc细胞。这一发现现在可以在一种新的肿瘤移植模型中进行测试，该模型结合了DsRed+ OTI-Tc细胞示踪，为研究免疫抑制剂在移植后恶性肿瘤中的差异作用开辟了道路。
BackgroundMammalian target of rapamycin (mTOR) inhibitors possess anticancer properties potentially useful in reducing posttransplantation malignancy. Besides controlling tumor-sensitive proliferative and angiogenic effects, mTOR influences transcription factors T-bet and Eomesodermin (Eomes) in CD8+ cytotoxic T cells (Tc), which are key in rejecting tumors, and allografts.MethodsTo study the role of mTOR in tumor and transplant immunity in an antigen-specific way, we used T-cell receptor transgenic B6. OTI recipients, B6. OVA. TG donors, and OVA-B16F10 melanoma cells. For tracking color-coded OTI-Tc cells associated with antitumor and alloimmunity in vivo, CD8-OTI transgenic reporter mice were created by crossbreeding DsRed-expressing B6. Nagy mice with B6. OTI mice.ResultsThe role of mTOR in regulating the differentiation and function of alloreactive Tc cells in vitro was explored by stimulating OTI-Tc cells with ovalbumin-transgenic antigen-presenting cells in the presence of rapamycin or tacrolimus. Rapamycin, but not tacrolimus, induced a pro-antitumor phenotypic shift from CD62L-CD44+ effector memory Tc cells to CD62L+ CD44+ central memory Tc cells, which featured up-regulated levels of T-bet and Eomes and preserved levels of interferon-γ and perforin. For future investigations, an in vivo model was established whereby DsRed+ OTI-Tc cells adoptively transferred into B6 mice bearing either a ovalbumin-transgenic mouse skin transplant or OVA-B16F10 tumor could be traced by fluorescence-activated cell sorting analysis as effector or memory Tc cells in transplant and tumor tissues.ConclusionmTOR, but not calcineurin, inhibition spares antitumoral memory Tc cells by distinctively regulating T-bet and Eomes. This finding is now testable in a new tumor transplant model, which incorporates DsRed+ OTI-Tc cell tracing, opening the way to study the differential effects of immunosuppressants in posttransplantation malignancy.