Kökrek Emel, Pir Pınar
Department of Molecular Biology and Genetics, Kadir Has University, Cibali, Kadir Has Cd., 34083 Fatih/Istanbul, Turkey.
Department of Bioengineering, Gebze Technical University, Cumhuriyet, 2254. Sk. No:2, 41400 Gebze/Kocaeli, Turkey.
J Leukoc Biol. 2025 Mar 14;117(3). doi: 10.1093/jleuko/qiae231.
The impact of aging on T cell subsets, specifically CD4+ and CD8+ T cells, leading to immune system dysfunction has been the focus of scientific investigation due to its potential to reverse age-associated deterioration. Transcriptomic and epigenomic studies have identified the primary regulators in T cell aging. However, comprehending the underlying dynamic mechanisms requires studying these proteins with their interactors. Here, we integrated single-cell RNA sequencing data of naive CD4+ and CD8+ T cells obtained from 3 different age groups with protein-protein and domain-domain interaction networks to predict and compare the transcriptional protein complexes and identify their capacity to explain age-associated variances. Our novel approach revealed significant effects of aging on the repertoire of complexes, which remains unchanged in naive CD4+ T cells, while in naive CD8+ T cells, it diminishes. In both cell types, there was major deregulation of complexes with the same composition, involving a range of transcription factors. This aging-associated deregulation is characterized by a specific set of protein complexes in naive CD4+ T cells, but this pattern is not observed in naive CD8+ T cells. SMAD3 and BCL11A complexes emerge as key markers in defining a trajectory in aging naive CD4+ T cells. These complexes can accurately distinguish between 3 different age groups, indicating their potential as targets. The direct link between SMAD3 and FOS complexes whose regulatory role has been previously implicated in aging and MBD3 as the novel key link between SMAD3 and BCL11A complexes implicates a coordinated mechanism in age-associated deregulation.
衰老对T细胞亚群，特别是CD4+和CD8+ T细胞的影响，导致免疫系统功能障碍，由于其具有逆转与年龄相关的衰退的潜力，一直是科学研究的重点。转录组学和表观基因组学研究已经确定了T细胞衰老的主要调节因子。然而，要理解潜在的动态机制，需要研究这些蛋白质与其相互作用分子。在这里，我们将从3个不同年龄组获得的初始CD4+和CD8+ T细胞的单细胞RNA测序数据与蛋白质-蛋白质和结构域-结构域相互作用网络整合起来，以预测和比较转录蛋白复合物，并确定它们解释与年龄相关差异的能力。我们的新方法揭示了衰老对复合物组成的显著影响，这在初始CD4+ T细胞中保持不变，而在初始CD8+ T细胞中则减少。在这两种细胞类型中，具有相同组成的复合物都存在主要的失调，涉及一系列转录因子。这种与衰老相关的失调在初始CD4+ T细胞中以一组特定的蛋白质复合物为特征，但在初始CD8+ T细胞中未观察到这种模式。SMAD3和BCL11A复合物成为定义衰老初始CD4+ T细胞轨迹的关键标志物。这些复合物可以准确区分3个不同的年龄组，表明它们作为靶点的潜力。SMAD3和FOS复合物之间的直接联系，其调节作用先前已被认为与衰老有关，以及MBD3作为SMAD3和BCL11A复合物之间的新关键联系，暗示了与年龄相关失调中的一种协调机制。
