更新于：2024-09-19

THEMIS2

更新于：2024-09-19

基本信息

别名

C1orf38、ICB-1、ICB1

+ [6]

简介

May constitute a control point in macrophage inflammatory response, promoting LPS-induced TLR4-mediated TNF production (PubMed:20644716). Determines the threshold for activation of B cells by low-affinity and low-avidity ligands via PLCG2 activation and its downstream pathways (By similarity).

关联

100 项与 THEMIS2 相关的临床结果

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100 项与 THEMIS2 相关的转化医学

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0 项与 THEMIS2 相关的专利（医药）

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项与 THEMIS2 相关的文献（医药）

2024-06-01·The Journal of Immunology

THEMIS2 Impairs Antitumor Activity of NK Cells by Suppressing Activating NK Receptor Signaling

Article

作者: Nabekura, Tsukasa ; Deborah, Elfira Amalia ; Shibuya, Akira ; Shibuya, Kazuko

AbstractNK cells are cytotoxic innate lymphocytes that play a critical role in antitumor immunity. NK cells recognize target cells by using a repertoire of activating NK receptors and exert the effector functions. Although the magnitude of activation signals through activating NK receptors controls NK cell function, it has not been fully understood how these activating signals are modulated in NK cells. In this study, we found that a scaffold protein, THEMIS2, inhibits activating NK receptor signaling. Overexpression of THEMIS2 attenuated the effector function of human NK cells, whereas knockdown of THEMIS2 enhanced it. Mechanistically, THEMIS2 binds to GRB2 and phosphorylated SHP-1 and SHP-2 at the proximity of activating NK receptors DNAM-1 and NKG2D. Knockdown of THEMIS2 in primary human NK cells promoted the effector functions. Furthermore, Themis2-deficient mice showed low metastatic burden in an NK cell–dependent manner. These findings demonstrate that THEMIS2 has an inhibitory role in the antitumor activity of NK cells, suggesting that THEMIS2 might be a potential therapeutic target for NK cell–mediated cancer immunotherapy.

2023-06-01·Cell Chemical Biology

IFNα primes cancer cells for Fusicoccin-induced cell death via 14-3-3 PPI stabilization

Article

作者: Kaschani, Farnusch ; Higuchi, Yusuke ; Choidas, Axel ; Centorrino, Federica ; Menninger, Sascha ; Wolf, Alexander ; Andrei, Sebastian A ; Ninck, Sabrina ; Heilmann, Geronimo ; Ottmann, Christian ; Eickhoff, Jan ; Kaiser, Markus ; Kato, Nobuo ; Klebl, Bert ; Andlovic, Blaž ; Arkin, Michelle ; Brunsveld, Luc

The natural product family of the fusicoccanes (FCs) has been shown to display anti-cancer activity, especially when combined with established therapeutic agents. FCs stabilize 14-3-3 protein-protein interactions (PPIs). Here, we tested combinations of a small library of FCs with interferon α (IFNα) on different cancer cell lines and report a proteomics approach to identify the specific 14-3-3 PPIs that are induced by IFNα and stabilized by FCs in OVCAR-3 cells. Among the identified 14-3-3 target proteins are THEMIS2, receptor interacting protein kinase 2 (RIPK2), EIF2AK2, and several members of the LDB1 complex. Biophysical and structural biology studies confirm these 14-3-3 PPIs as physical targets of FC stabilization, and transcriptome as well as pathway analyses suggest possible explanations for the observed synergistic effect of IFNα/FC treatment on cancer cells. This study elucidates the polypharmacological effects of FCs in cancer cells and identifies potential targets from the vast interactome of 14-3-3s for therapeutic intervention in oncology.

2023-01-30·Disease Markers

Screening of Biomarkers in Liver Tissue after Bariatric Surgery Based on WGCNA and SVM-RFE Algorithms

Article

作者: Liu, Zhixin ; Jiang, Yicheng ; Yang, Haojun ; Wang, Yu ; Chen, Shuai ; Jiao, Yuwen ; Tang, Liming

As the most common chronic liver disease around the world, nonalcoholic fatty liver disease (NAFLD) has a close connection with obesity, diabetes, and metabolic syndrome. Bariatric surgery (BS) is considered to be the most effective treatment for NAFLD. However, the regulatory mechanism of hepatic lipid metabolism after BS remains poorly elucidated. By analyzing two transcriptome datasets regarding liver tissues after BS, namely, GSE83452 and GSE106737, we acquired 110 differentially expressed genes (DEGs). By further analysis of DEGs in terms of the weighted gene coexpression network analysis (WGCNA) and support vector machine-recursive feature elimination (SVM-RFE) algorithms, we identified four crucial genes participating in the regulation of hepatic lipid metabolism: SRGN, THEMIS2, SGK1, and FPR3. In addition, the results of gene set enrichment analysis (GSEA) showed that BS can activate immune-related regulatory pathways and change immune cell infiltration levels. Finally, through cellular level studies, we found that the silencing of SRGN affects the expression of SREBP-1, SIRT1, and FAS during adipogenesis in the liver and the formation of lipid droplets in the liver. In summary, the immune system in the liver is activated after BS, and SRGN participates in the regulation of hepatic lipid metabolism.

项与 THEMIS2 相关的新闻（医药）

2022-09-25

·佰傲谷BioValley

干细胞样记忆T细胞：标志物、活性、应用开发

异质性记忆T（TM）细胞根据表型分子的不同，可分为干细胞样记忆T细胞（TSCM）、中央记忆T (TCM)细胞和效应记忆T (TEM)细胞等不同亚群。人类不同T细胞亚群的特征性表面标记Cell Immunol. 2021TSCM的生物学特性及应用TSCM细胞被认为是分化程度最低、寿命较长的TM细胞群，具有很强的自我更新能力、长期持久性、增殖能力和抗肿瘤活性，并能多向其他记忆细胞子集分化。分化程度低的具体证据包括TSCM细胞可以在体内启动时直接从注入的naïve T (TN)细胞中分化；TN和TSCM细胞，而不是TCM或TEFF细胞，能够重建包括TSCM细胞在内的记忆T细胞亚群的全部异质性；TN和TSCM细胞之间差异表达的基因只有75个，而TCM和TEM细胞则分别为157和226个。符合CD8+T细胞渐进式分化的框架路径：TN→TSCM→TEM/EFFCD8+ T细胞的分化途径Clin Immunol. 2022其表面标志的特征包括表达TN细胞的特征标记：CCR7+、CD45RA+、CD45RO−、CD62L+、CD27+、CD28+和IL-7RA+ (CD127)；表达记忆细胞的特征标记：CD95+、IL-2Rβ+ (CD122)、CXCR3+和LFA-1+；表达更多的BCL-2、CXCR4较少表达CD38和CD31；TSCM和TCM细胞之间的差异目前认为归因于细胞群中CCR7+GZMK+PD-1+TIGIT+亚群的比例不同，该类亚群被称为T祖细胞衰竭样细胞。长期持久性、增殖能力和抗肿瘤活性的表现包括：该细胞群中约60%细胞的表型特征不随时间变化；黄热病(YF)疫苗注射后，早期就可检测到YF特异性CD8+ TSCM细胞，并稳定维持了25年以上；在TCR刺激后，CD8+ TSCM细胞也能快速反应并产生和释放IFN-γ、IL-2和TNF-α，其效应功能与传统记忆T细胞相似。TSCM的抗肿瘤、抗病毒作用血液瘤和病毒感染：目前认为过继细胞转移治疗(ACT)最终产物中，CD4+/ CD8+细胞比例可能影响其抗肿瘤疗效。了解TSCM中CD4+亚群和CD8+亚群的作用对其潜在应用开发也同样重要。CD4+TSCM细胞在免疫应答中承担不同的作用，可以通过与CD8+TSCM细胞相似的机制进行编程和生成。已有的应用包括：已知长期治疗的HIV患者体内的CD4+TSCM细胞可作为细胞HIV-1病毒储存库；成人T细胞白血病(ATL)模型中，CD4+TSCM细胞可向TCM和TEM细胞定向分化，有利于ATL病毒克隆的保存和产生。CD4+TSCM细胞被评价为结肠直肠癌辅助诊断和早期筛查的指标，敏感性和特异性高。实体瘤：TSCM细胞在肿瘤微环境(TME)特别是实体癌中抗肿瘤作用的确切机制仍有待研究，因为目前普遍认为，在TME中持续的肿瘤抗原刺激条件下，T细胞采取了不同的分化途径。间皮瘤小鼠模型：CD8+ TSCM细胞具有增强的抗肿瘤活性，且对小鼠的治疗效果优于同样间皮素特异性CD8+的TCM或TEM细胞；黑色素瘤小鼠模型：移植TSCM细胞在体内产生了更强的抗肿瘤效果，对肿瘤生长的抑制作用更持久，最终使总生存期(OS)显著提高；T细胞衰竭的影响与治疗策略：TSCM细胞同样会在持续的肿瘤抗原刺激下进入功能失调状态，即“T细胞衰竭”（T cell exhaustion）。衰竭T细胞（TEX）的功能特征为：效应功能丧失、抑制受体表达升高和持续、表观遗传和转录谱改变以及独特的代谢，失去其干细胞样特性，导致其增殖情况缩短和抗肿瘤功能受损。T细胞衰竭可能在慢性感染和癌症控制中起着至关重要的作用，在某些情况下可能作为一种机制，保护组织免受过强免疫病理损伤，在疾病控制和免疫病理之间建立平衡。因此，如何避免T细胞衰竭或“重振”TEX细胞，使其呈现更“干细胞样”的状态，可能是进一步突破免疫疗法疗效不理想困境的关键。目前已有证据表明在衰竭发育过程中起关键作用的转录因子包括TCF-1、PRDM1、T- bet、Eomes、NFAT、NR4A、IRF4和BATF。TSCM细胞的诱导增殖方法若要将TSCM细胞用于细胞疗法中，则需要诱导出足够的数量。TSCM分化上下游Cell Immunol. 2021 目前研究中的诱导方向包括细胞因子的操纵、微环境中的代谢因子、TCR信号强度以及信号通路的激活或抑制。Clin Immunol. 2022 Aug;241:109078. Epub 2022 Jul 15. doi: 10.1016/j.clim.2022.109078.（1）细胞因子：γ链细胞因子主要通过JAK-STAT和PI3K-AKT-mTOR途径发挥作用。IL-2被广泛用于ACT的细胞扩增。但同时，IL-2也不可避免地驱动效应子分化，抑制记忆发育，控制特异性抑制受体的表达，从而降低长期抗肿瘤疗效；IL-15对TSCM细胞的增殖至关重要，与其在CD8+ T细胞的内稳态和增殖中的作用一致；IL-7作为T细胞稳态调节剂，优先保存TSCM细胞的干细胞样表型；IL-7和IL-15在促进TN/TSCM细胞增殖方面优于Gsk-3β抑制剂；IL-21与IL-7和IL-15协同作用，促进记忆T细胞和naïve T细胞的增殖和存活；在临床前和临床研究中，IL-21和ICBs也被证明是诱导TSCM细胞表型的可行策略。（2）信号通路与代谢：目前尚不确定TSCM细胞的命运是否仅受到某一条唯一且特定的信号通路影响。Wnt-β-catenin通路：早期的TSCM细胞生成可能是通过Gsk-3β抑制剂激活Wnt-β-catenin信号通路，下游抑制β-catenin的降解，使β-catenin在细胞质中积累，后者转移到细胞核与TCF-1/LEF1转录因子结合；但是体外实验显示，Gsk-3β抑制同样增加了TSCM细胞介导的肿瘤细胞毒性；TCF-1：通过与Eomes的调控区域结合，增加自身和IL-2R的表达，从而促进生产分化较低的干细胞样细胞状态和内稳态。小鼠模型显示：TCF-1缺陷的CD8+ T细胞不能在小鼠体内产生记忆前体和TCM细胞。Notch信号通路：可使致敏CD4+ T细胞增殖，调节各种Th亚群的分化和应答。体外实验显示：通过与表达Notch配体的基质细胞共培养，iTSCM细胞是从激活的CD4+和CD8+ T细胞中生成，而非naïve T细胞。与传统的CAR-T细胞相比，Notch诱导CAR-iTSCM细胞和Foxm1诱导CAR-iTSCM细胞的通路都具有更强的抗肿瘤潜能。FAO代谢：TSCM和其他T细胞一样，依赖FAO作为ATP合成的主要来源。乳酸脱氢酶(LDH)被证明是增加TSCM细胞数量和提高过继移植后体内抗肿瘤活性的机制。（3）TCR和共刺激信号强度：肽/MHC-TCR相互作用的持续时间和强度可以影响TCR识别的下游，并影响T细胞的分化轨迹：经实验证实，通过MEK抑制来操纵MAPK通路可促进TSCM细胞的生成；小鼠模型显示，含有不同比例TSCM细胞的细胞群注射到肝细胞癌小鼠模型后，会产生不同的抗肿瘤作用。TSCM/TCM细胞比例较高，则TET499细胞增殖较多，这与TCR信号较弱有关；转导了4-1BB共刺激信号的第二代CAR-T慢病毒载体可诱导高水平的TCM/TSCM表型；TNFRSF中其他T细胞共刺激分子的激动剂，如CD27、OX40、TNFR2、CD40和GITR同样具有此类效果。例如CD40的激活促进了HPV16特异性TSCM细胞的形成，增强了体内长期抗肿瘤能力，这被认为与Wnt/ β-catenin信号的激活有关，并可能阻止HPV感染向宫颈癌发展。刺激时间也与T细胞命运有关：与长时间的刺激相比，CD3 /CD28抗体的短暂刺激为T细胞激活提供了第一和第二信号，为CD8+ T细胞提供了更好的增殖信号。而短暂刺激扩增的CD8+ T细胞具有更丰富的TSCM亚群，表现出更强的细胞因子生产能力。小结TSCM应用的疾病领域包括：肿瘤：血液瘤研究较多，如B细胞恶性肿瘤、急性淋巴细胞白血病、Raji-ffLuc淋巴瘤等。实体瘤包括非小细胞肺癌、肾细胞癌和结肠癌等；自身免疫性疾病：选择性耗尽自反应性TSCM亚群可能是治疗自身免疫性疾病的一种有前途和可行的选择。目前有尝试的适应症包括获得性再生障碍性贫血、系统性红斑狼疮、镰状细胞病、免疫性血小板减少症(ITP)、1型糖尿病(T1D)和自身免疫性葡萄膜炎等；HIV或SIV；其他传染性疾病疫苗：由于TSCM提供了长期免疫记忆，测量疫苗诱导的TSCM可能更准确地预测疫苗的有效性。目前尚无正式进入临床阶段的TSCM细胞疗法，主要还是受限于从外周血CD8+T细胞中提取和增殖TSCM亚群的时间和技术难点。参考文献：1. Wang F, Cheng F, Zheng F. Stem cell like memory T cells: A new paradigm in cancer immunotherapy. Clin Immunol. 2022 Aug;241:109078. doi: 10.1016/j.clim.2022.109078. Epub 2022 Jul 15. PMID: 35840054.2. Wang Y, Qiu F, Xu Y, Hou X, Zhang Z, Huang L, Wang H, Xing H, Wu S. Stem cell-like memory T cells: The generation and application. J Leukoc Biol. 2021 Dec;110(6):1209-1223. doi: 10.1002/JLB.5MR0321-145R. Epub 2021 Aug 17. PMID: 34402104.3. Gao S, Liang X, Wang H, Bao B, Zhang K, Zhu Y, Shao Q. Stem cell-like memory T cells: A perspective from the dark side. Cell Immunol. 2021 Mar;361:104273. doi: 10.1016/j.cellimm.2020.104273. Epub 2021 Jan 5. PMID: 33422699.近期热门视频更多精彩视频，尽在佰傲谷视频号，欢迎关注~本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀点亮在看，传递信息♥

细胞疗法免疫疗法抗体疫苗