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| 1 | 机械力诱导MHC-Ⅰ构象变化增强TCR抗原识别及T细胞活化显示文摘CD8+T细胞主要通过T细胞表面受体(T cell recep tor,TCR)识别并与Ⅰ型主要组织性复合物提呈的抗原(pMHC-Ⅰ)相互作用[1]。TCR对刺激型抗原的识别在CD8+T细胞毒性和适应性免疫中发挥着关键作用。许多证据表明机械力可以延长TCR与刺激性pMHC作用的键合时间(bond lifetime)形成抗原特异性逆锁键(catch bond)[2],并且这种逆锁键对抗原识别非常重要。然而,机械力调控TCR抗原识别的具体结构机制仍不清楚。通过分子动力学模拟、单分子生物膜力学探针、磁镊、T细胞活化实验和动物模型对此问题展开了系统的研究[4]。发现作用在TCR-pMHC-Ⅰ复合体上的拉力可以作用在TCR-pMHC-Ⅰ复合体上的拉力可以打破MHC-I分子内部α1-α2和β2结构域间的相互作用,导致α1-α2结构域旋转并发生构象变化。力诱导的MHC-I构象变化可以进一步别构地调节TCR与刺激性抗原肽及α1-α2结构域的构象及相互作用,诱导产生新的氢键,增强TCR-pMHC-Ⅰ之间的键合时间,但并不能增强TCR与抑制性pMHC-Ⅰ之间的作用。当用点突变阻断这些新形成的氢键,或者α1-α2和β2结构域被二硫键锁住时,最佳力诱导的TCR-pMHC-Ⅰ作用的键合时间明显缩短并且T细胞的活化受到抑制。另外,在人TCR和HLA-A2相互作用中发现了类似机制,并且与肿瘤相关的HLA-A2点突变[3]可以通过限制HLA-A2α1--α2和β2结构域之间的构象打开减弱TCR对肿瘤抗原的识别及T细胞的功能。研究结果表明,机械力诱导的MHC-I构象变化对TCR抗原识别和T细胞活化非常重要,进一步地阐明了机械力调控TCR抗原识别机制,为临床肿瘤的免疫治疗和药物设计提供了新思路和新靶点。 | Peng Wu Tongtong Zhang Baoyu Liu Panyu Fei Lei Cui Rui Qin Huaying Zhu Danmei Yao Ryan Martinez Wei Hu Chenyi An Yong Zhang Junwei Liu Weiwei Yin Jie Sun Chun Zhou Xun Zeng Jianan Wang Brian Evavold Cheng Zhu Jizhong Lou Wei Chen | 2019 | 医用生物力学2019，34，A01： | 0 |
| 2 | Development and Characterization of Nanobody-Derived CD47 Theranostic Pairs in Solid Tumors显示文摘Overexpression of CD47 is frequently observed in various types of human malignancies,inhibiting myeloidmediated elimination of tumor cells and affecting the prognosis of cancer patients.By mapping biomarker expression,immuno-positron emission tomography has been increasingly used for patient screening and response monitoring.By immunization alpacas with recombinant human CD47,we prepared a CD47-targeting nanobody C2 and developed[^(68)Ga]Ga-NOTA-C2,followed by an exploration of the diagnostic value in CD47-expressing tumor models including gastric-cancer patient-derived xenograft models.By fusing C2 to an albumin binding domain(ABD),we synthesized ABDC2,which had increased in vivo half-life and improved targeting properties.We further labeled ABDC2 with^(68)Ga/^(89)Zr/177Lu to develop radionuclide theranostic pairs and evaluated the pharmacokinetics and theranostic efficacies of the agents in cell-and patient-derived models.Both C2 and ABDC2 specifically reacted with human CD47 with a high KD value of 23.50 and 84.57 pM,respectively.[^(68)Ga]Ga-NOTA-C2 was developed with high radiochemical purity(99>%,n=4)and visualized CD47 expression in the tumors.In comparison to the rapid renal clearance and short half-life of[^(68)Ga]Ga-NOTA-C2,both[^(68)Ga]Ga-NOTA-ABDC2 and[^(89)Zr]Zr-DFOABDC2 showed prolonged circulation and increased tumor uptake,with the highest uptake of[^(89)Zr]Zr-DFO-ABDC2 occurring at 72 h post-injection.Moreover,[177Lu]Lu-DOTA-ABDC2 radioimmunotherapy suppressed the tumor growth but was associated with toxicity,warranting further optimization of the treatment schedules.Taken together,we reported a series of nanobody-derived CD47-targeted agents,of which[^(68)Ga]Ga-NOTA-C2 and[^(89)Zr]Zr-DFO-ABDC2 are readily translatable.Optimization and translation of CD47-targeted theranostic pair may provide new prospects for CD47-targeted management of solid tumors. | You Zhang Di Zhang Shuxian An Qiufang Liu Chenyi Liang Juan Li Ping Liu Changfeng Wu Gang Huang Weijun Wei Jianjun Liu | 2023 | Research2023，，4： | 0 |
| 3 | Multiplexed single-molecule force spectroscopy for dissecting biophysical regulation of membrane receptors functions on live cells显示文摘Complex physical cues including two-dimensional membrane environment,dynamic mechanical force,and bioelectric activity inevitably affect membrane receptor functions.Multiplexed single-molecule force spectroscopy(SMFS)techniques with the capability of live-cell measurements are essential to systemically dissect receptor’s functions under complex biophysical regulation.In this review,we summarize recent progress of live-cell based SMFS techniques and specifically focus on the progress of SMFS on the biomembrane force probe with enhanced mechanical stability and multiplexed capability of fluorescence imaging.We further suggest the necessity of developing multiplexed SMFS techniques with simultaneous bioelectric regulation capability to investigate membrane potential regulated membrane receptor functions.These state-of-art multiplexed SMFS techniques will dissect membrane receptors functions in a systematic biophysical angle,resolving the biochemical,biomechanical and bioelectrical regulatory mechanisms in physiologically relevant conditions. | Chenyi An Wei Chen | 2021 | Biophysics Reports2021，7，5： | 0 |
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