CD4+ T-Cell Activation Prompts Suppressive Function by Extracellular Vesicle-Associated MicroRNAs

Abstract

MicroRNAs (miRNAs), small non-coding molecules targeting messenger RNAs and inhibiting protein translation, modulate key biological processes, including cell growth and development, energy utilization, and homeostasis. In particular, miRNAs control the differentiation, survival, and activation of CD4+ T conventional (Tconv) cells, key players of the adaptive immunity, and regulate the physiological response to infections and the pathological loss of immune homeostasis in autoimmunity. Upon T-cell receptor (TCR) stimulation, the described global miRNA quantitative decrease occurring in T cells is believed to promote the acquisition of effector functions by relaxing the post-transcriptional repression of genes associated with proliferation and cell activity. MiRNAs were initially thought to get downregulated uniquely by intracellular degradation; on the other hand, miRNA secretion via extracellular vesicles (EVs) represents an additional mechanism of rapid downregulation. By focusing on molecular interactions by means of graph theory, we have found that miRNAs released by TCR-stimulated Tconv cells are significantly enriched for targeting transcripts upregulated upon stimulation, including those encoding for crucial proteins associated with Tconv cell activation and function. Based on this computational approach, we present our perspective based on the following hypothesis: a stimulated Tconv cell will release miRNAs targeting genes associated with the effector function in the extracellular space in association with EVs, which will thus possess a suppressive potential toward other Tconv cells in the paracrine environment. We also propose possible future directions of investigation aimed at taking advantage of these phenomena to control Tconv cell effector function in health and autoimmunity.

Integrated Strategies for a Holistic View of Extracellular Vesicles

“…The need for data integration originates from the holistic view of the cell’s response to different conditions, and data-derived system biology approaches could represent a powerful strategy for a comprehensive understanding of the EVs’ complexity and their role in cellular communication. 1 , 6 , 27 , 19 The major challenges in evaluating EVs as biological systems concern their high dimensionality (many players involved) and connectivity (many connections between players). To address these difficulties, as for omics profiles, holistic methods based on network analysis represent a tool for associating heterogeneous data and unraveling the tangle of molecular relationships in which EVs may be involved.…”

“… 1 , 6 , 27 , 19 Noteworthy, in this context, novel approaches put an emphasis on the topology of the reconstructed network models with the purpose to detect pathways affected by the treatment of EVs and hubs as molecules targeted by EVs. 6 , 27 …”

“…Although the correlation of multiple omics data reflecting the EVs’ cargo content represents a key aspect for extracting distinctive signatures, , as well as to predict the effect of EVs on target cells, , their integration with other types of EV data and findings can improve the understanding of the relationships among structures, cargos, and functions mediated by EVs. The need for data integration originates from the holistic view of the cell’s response to different conditions, and data-derived system biology approaches could represent a powerful strategy for a comprehensive understanding of the EVs’ complexity and their role in cellular communication. ,,, The major challenges in evaluating EVs as biological systems concern their high dimensionality (many players involved) and connectivity (many connections between players).…”

“…Although the correlation of multiple omics data reflecting the EVs’ cargo content represents a key aspect for extracting distinctive signatures, , as well as to predict the effect of EVs on target cells, , their integration with other types of EV data and findings can improve the understanding of the relationships among structures, cargos, and functions mediated by EVs. The need for data integration originates from the holistic view of the cell’s response to different conditions, and data-derived system biology approaches could represent a powerful strategy for a comprehensive understanding of the EVs’ complexity and their role in cellular communication. ,,, The major challenges in evaluating EVs as biological systems concern their high dimensionality (many players involved) and connectivity (many connections between players). To address these difficulties, as for omics profiles, holistic methods based on network analysis represent a tool for associating heterogeneous data and unraveling the tangle of molecular relationships in which EVs may be involved.…”

“…Cell–cell communication is an essential process in living organisms, and its dysregulation may be responsible for various diseases. The EVs’ heterogeneous molecular cargo and its role in immunomodulation , have inspired researchers to find the link among EVs, the immune system, and tumor development and progression . Yet, the link between EVs and the immune system and the role of EVs, in general, has been related to plenty of diseases, including metabolic, neurodegenerative, and cardiovascular ones, so that in parallel, due to their presence in biological fluids, their clinical relevance for diagnostic and prognostic purposes is rapidly increasing as is their relevance as therapeutic targets and agents .…”