小柯机器人

英国伦敦大学学院Mala K. Maini等研究人员合作发现，组织CD14+CD8⁺T细胞被髓系细胞重编程，并被LPS调节。2023年1月25日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现不同比例的CD8⁺T细胞在CD14和其他原型髓系膜蛋白的人肝脏共染中区隔化，并在肝脏2区的CD14^high髓系细胞附近富集。CD14⁺CD8⁺T细胞在同种异体肝移植、肝病毒特异性和肿瘤浸润反应以及肝硬化腹水中优先聚集在供体池内。在结合TCR后，CD14⁺CD8⁺T细胞表现出更高的周转率、活化和组成型免疫调节特征，并在半体内中具有高稳态IL-10和IL-2的产生，以及增强的抗病毒/抗肿瘤效应功能。这种CD14⁺CD8⁺T细胞的特征可以通过从单核吞噬细胞获取膜蛋白（包括脂多糖受体复合物）来概括，从而在体外由tcr重定向的T细胞增强肿瘤杀伤。CD14⁺CD8⁺T细胞表达整合素和趋化因子受体，这些受体有利于它们与局部基质的相互作用，从而促进它们通过CXCL12的诱导。脂多糖还可以增加CD14⁺CD8⁺T细胞在体外和体内的频率，并使其功能偏向于趋化和再生细胞因子的产生。因此，肠-肝轴的细菌产物和组织间质因子可以通过驱动具有免疫调节能力的CD8⁺T细胞的髓系指令来调节肝脏免疫。

据介绍，肝脏沐浴在细菌产物中，包括从肠门静脉血管运输的脂多糖，但保持一种被持久性病原体和肿瘤利用的耐受状态。目前需要更好地理解介导这种耐受性的细胞基础，同时允许转向免疫或免疫病理，从而成功地对肝脏疾病进行免疫治疗。

附：英文原文

Title: Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS

Author: Pallett, Laura J., Swadling, Leo, Diniz, Mariana, Maini, Alexander A., Schwabenland, Marius, Gasull, Adri Dalmau, Davies, Jessica, Kucykowicz, Stephanie, Skelton, Jessica K., Thomas, Niclas, Schmidt, Nathalie M., Amin, Oliver E., Gill, Upkar S., Stegmann, Kerstin A., Burton, Alice R., Stephenson, Emily, Reynolds, Gary, Whelan, Matt, Sanchez, Jenifer, de Maeyer, Roel, Thakker, Clare, Suveizdyte, Kornelija, Uddin, Imran, Ortega-Prieto, Ana M., Grant, Charlotte, Froghi, Farid, Fusai, Giuseppe, Lens, Sabela, Prez-del-Pulgar, Sofia, Al-Akkad, Walid, Mazza, Giuseppe, Noursadeghi, Mahdad, Akbar, Arne, Kennedy, Patrick T. F., Davidson, Brian R., Prinz, Marco, Chain, Benjamin M., Haniffa, Muzlifah, Gilroy, Derek W., Dorner, Marcus, Bengsch, Bertram, Schurich, Anna, Maini, Mala K.

Issue&Volume: 2023-01-25

Abstract: The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1,2,3,4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins—including the lipopolysaccharide receptor complex—from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut–liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.

DOI: 10.1038/s41586-022-05645-6

Source: https://www.nature.com/articles/s41586-022-05645-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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