Optical Control of CD8(+) T Cell Metabolism and Effector Functions.
Optical Control of CD8(+) T Cell Metabolism and Effector Functions.
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DOI：
10.3389/fimmu.2021.666231
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发表时间：
2021
影响因子：
7.3
通讯作者：
Kim M
中科院分区：
文献类型：
--
作者：
Amitrano AM;Berry BJ;Lim K;Kim KD;Waugh RE;Wojtovich AP;Kim M
虽然癌症免疫疗法对血液恶性肿瘤有效，但对实体瘤的有效性较低，部分原因是肿瘤微环境（TME）中存在显著的代谢挑战，其中浸润的CD 8 + T细胞面临与癌细胞激烈竞争有限的营养物质。TME中的强代谢抑制通常与受损的T细胞募集至肿瘤部位和通过T细胞耗竭的低应答效应器功能相关。越来越多的证据表明，线粒体在CD 8 + T细胞活化、效应子功能和肿瘤持久性中起关键作用。在这项研究中，我们发现，在小鼠和人CD 8 + T细胞活化过程中，整体线粒体功能（包括线粒体质量和膜电位）均有所增加。CD 8 + T细胞线粒体膜电位与颗粒酶B和IFN-γ的产生密切相关，表明线粒体在效应T细胞功能中的重要性。此外，在ICAM-1和CXCL 12上迁移的活化的CD 8 + T细胞比静止的CD 8 + T细胞消耗更多的氧。抑制线粒体呼吸降低了CD 8 + T细胞迁移的速度，表明线粒体代谢在CD 8 + T细胞迁移中的重要性。表达我们新开发的“OptoMito-On”的CD 8 + T细胞的远程光学刺激成功地增强了线粒体ATP的产生，并改善了整体CD 8 + T细胞的迁移和效应功能。我们的研究为线粒体膜电位对CD 8 + T细胞效应功能的影响提供了新的见解，并展示了一种新型光遗传学技术的发展，该技术以出色的特异性和时空分辨率远程控制靶肿瘤部位的T细胞代谢和效应功能。
Although cancer immunotherapy is effective against hematological malignancies, it is less effective against solid tumors due in part to significant metabolic challenges present in the tumor microenvironment (TME), where infiltrated CD8+ T cells face fierce competition with cancer cells for limited nutrients. Strong metabolic suppression in the TME is often associated with impaired T cell recruitment to the tumor site and hyporesponsive effector function via T cell exhaustion. Increasing evidence suggests that mitochondria play a key role in CD8+ T cell activation, effector function, and persistence in tumors. In this study, we showed that there was an increase in overall mitochondrial function, including mitochondrial mass and membrane potential, during both mouse and human CD8+ T cell activation. CD8+ T cell mitochondrial membrane potential was closely correlated with granzyme B and IFN-γ production, demonstrating the significance of mitochondria in effector T cell function. Additionally, activated CD8+ T cells that migrate on ICAM-1 and CXCL12 consumed significantly more oxygen than stationary CD8+ T cells. Inhibition of mitochondrial respiration decreased the velocity of CD8+ T cell migration, indicating the importance of mitochondrial metabolism in CD8+ T cell migration. Remote optical stimulation of CD8+ T cells that express our newly developed “OptoMito-On” successfully enhanced mitochondrial ATP production and improved overall CD8+ T cell migration and effector function. Our study provides new insight into the effect of the mitochondrial membrane potential on CD8+ T cell effector function and demonstrates the development of a novel optogenetic technique to remotely control T cell metabolism and effector function at the target tumor site with outstanding specificity and temporospatial resolution.
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影响因子：
29
作者：
Cascone T;McKenzie JA;Mbofung RM;Punt S;Wang Z;Xu C;Williams LJ;Wang Z;Bristow CA;Carugo A;Peoples MD;Li L;Karpinets T;Huang L;Malu S;Creasy C;Leahey SE;Chen J;Chen Y;Pelicano H;Bernatchez C;Gopal YNV;Heffernan TP;Hu J;Wang J;Amaria RN;Garraway LA;Huang P;Yang P;Wistuba II;Woodman SE;Roszik J;Davis RE;Davies MA;Heymach JV;Hwu P;Peng W
通讯作者：
Peng W
影响因子：
5.6
作者：
Berry BJ;Trewin AJ;Amitrano AM;Kim M;Wojtovich AP
通讯作者：
Wojtovich AP
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M
影响因子：
14.5
作者：
Fischer, Lindsey R.;Igoudjil, Anissa;Glass, Jonathan D.
通讯作者：
Glass, Jonathan D.