Biwott Kipchumba, Singh Parvind, Baráth Sándor, Nyariki James Nyabuga, Hevessy Zsuzsanna, Bacso Zsolt
Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary; Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen 4032, Hungary; Department of Biochemistry and Biotechnology, Technical University of Kenya, Kenya.
Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
Biomed Pharmacother. 2025 Jan;182:117780. doi: 10.1016/j.biopha.2024.117780. Epub 2024 Dec 30.
ABCB1/MDR-1/P-glycoprotein (Pgp) is an ABC transporter responsible for cancer cell multi-drug resistance. It is expressed in cytotoxic T lymphocytes (CTL). Eliminating sensitive cancer cells during high-dose chemotherapy can also damage immune cells. Our study aimed to assess which maturing human CD8 + CTL memory subsets may be affected based on their Pgp protein expression. In an in vitro CTL differentiation model system, we tracked the maturation of naive, effector, and memory cells and the expression of Pgp. This system involves co-culturing blood lymphocytes with proliferation-inhibited JY antigen-presenting B-lymphoblastoid cells expressing HLA-I A2. These JY-primed maturing CTLs were TCR-activated using beads, and the effect of the maturation-modifying JAK1/2 inhibitor ruxolitinib was examined. Multidimensional analysis identified six major CTL subsets: naive, young memory (Tym), stem cell memory (Tscm), central memory (Tcm), effector memory (Tem), and effectors (Te). These subsets were further divided into thirteen specific subsets: TymCD127 + , TymCD127-, Tscm, TcmCD95 + , TcmCD73 +CD95 + , TcmCD95+CD127 + , TcmPD1 + , TemCD95 + , TemraCD127 + , TemraCD127-, TeCD95 + , and TeCD73 +CD95 + . Pgp expression was detectable in naïve cells and dynamically changed across the thirteen identified subsets. Increased Pgp was detected in young memory T cells and in Tscm, TcmCD95 + , and TcmPD1 + human CTL subsets. Unlike other transiently appearing memory cells, the number of cells in these core Pgp-expressing memory subsets stabilized by the end of the contraction phase. Ruxolitinib treatment downregulated effector T-cell polarization while upregulating small memory subsets expressing Pgp. In conclusion, activation increased Pgp expression, whereas ruxolitinib treatment preserved small early and late memory subset core that primarily expressed Pgp.
ABCB1/MDR-1/P-糖蛋白（Pgp）是一种负责癌细胞多药耐药性的ABC转运蛋白。它在细胞毒性T淋巴细胞（CTL）中表达。在大剂量化疗期间清除敏感癌细胞也会损害免疫细胞。我们的研究旨在评估哪些成熟的人类CD8⁺CTL记忆亚群可能因其Pgp蛋白表达而受到影响。在体外CTL分化模型系统中，我们追踪了初始、效应和记忆细胞的成熟过程以及Pgp的表达。该系统涉及将血液淋巴细胞与表达HLA-I A2的增殖抑制型JY抗原呈递B淋巴母细胞共培养。这些经JY致敏的成熟CTL使用磁珠进行TCR激活，并检测成熟修饰型JAK1/2抑制剂鲁索替尼的作用。多维分析确定了六个主要的CTL亚群：初始、年轻记忆（Tym）、干细胞记忆（Tscm）、中央记忆（Tcm）、效应记忆（Tem）和效应细胞（Te）。这些亚群进一步分为13个特定亚群：TymCD127⁺、TymCD127⁻、Tscm、TcmCD95⁺、TcmCD73⁺CD�5⁺、TcmCD95⁺CD127⁺、TcmPD1⁺、TemCD95⁺、TemraCD127⁺、TemraCD127⁻、TeCD95⁺和TeCD73⁺CD95⁺。在初始细胞中可检测到Pgp表达，并且在13个已确定的亚群中动态变化。在年轻记忆T细胞以及Tscm、TcmCD95⁺和TcmPD1⁺人类CTL亚群中检测到Pgp增加。与其他短暂出现的记忆细胞不同，这些核心表达Pgp的记忆亚群中的细胞数量在收缩期结束时稳定下来。鲁索替尼治疗下调效应T细胞极化，同时上调表达Pgp的小记忆亚群。总之，激活增加了Pgp表达，而鲁索替尼治疗保留了主要表达Pgp的早期和晚期小记忆亚群核心。
