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


Posted: 2021-11-15 20:00:00
Front Cell Dev Biol . 2021 Oct 27;9:753884. doi: 10.3389/fcell.2021.753884. eCollection 2021. Affiliations Expand Affiliations 1 Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), Milan, Italy. 2 Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy. 3 Unitá di Neuroimmunologia, IRCCS Fondazione Santa Lucia, Roma, Italy. 4 IRCCS MultiMedica, Milan, Italy. 5 Treg Cell Laboratory, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universitá Degli Studi di Napoli "Federico II", Naples, Italy. Item in Clipboard Dario Di Silvestre et al. Front Cell Dev Biol. 2021. Show details Display options Display options Format Front Cell Dev Biol . 2021 Oct 27;9:753884. doi: 10.3389/fcell.2021.753884. eCollection 2021. Affiliations 1 Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), Milan, Italy. 2 Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy. 3 Unitá di Neuroimmunologia, IRCCS Fondazione Santa Lucia, Roma, Italy. 4 IRCCS MultiMedica, Milan, Italy. 5 Treg Cell Laboratory, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universitá Degli Studi di Napoli "Federico II", Naples, Italy. Item in Clipboard CiteDisplay options Display options Format 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. Keywords: CD4+ T cells; cell activation; exosomes; extracellular vesicles; microRNA. Copyright © 2021 Di Silvestre, Garavelli, Procaccini, Prattichizzo, Passignani, De Rosa, Mauri, Matarese and de Candia. Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Figures FIGURE 1 (A) Heatmap showing miRNA expression… FIGURE 1 (A) Heatmap showing miRNA expression ( n = 60) in extracellular vesicles released… FIGURE 1 (A) Heatmap showing miRNA expression (n = 60) in extracellular vesicles released by in vitro TCR-stimulated Tconv cells (isolated from five healthy donors). Each molecule was normalized by miRNA global mean and ranked based on relative mean expression value from the most to the least expressed. (B) Bar histogram showing the number of miRNA targets (among those transcripts either upregulated, red, or downregulated, blue, following TCR stimulation) for each of the 60 detectable Tconv-derived EV-miRNAs, ranked based on target total number. (C) Box plots comparing the number of miRNA–target interactions (degree, upper panel) and density distribution of the interactions (lower panel) distinguishing the transcripts (targets) for being either upregulated (red) or downregulated (blue) following TCR stimulation (Student’s t-test, p < 0.0001). (D) MiRNAs–targets network reconstructed considering only transcripts upregulated following TCR stimulation. (E) Protein–protein interaction HUBS selected by considering Betweenness, Bridging, and Centroid centralities; the gene name size is proportional to the number of miRNAs targeting it. FIGURE 2 Cartoon summarizing our hypothesis: upon… FIGURE 2 Cartoon summarizing our hypothesis: upon TCR stimulation, a naïve T cell (blue, left)… FIGURE 2 Cartoon summarizing our hypothesis: upon TCR stimulation, a naïve T cell (blue, left) downregulates miRNAs (also) by EV-associated release into the extracellular space (blue to red gradient, upper), thus leading to proper mRNA expression in activated T cell (red, right). EV-miRNAs can be up-taken by an adjacent T cell (red to blue gradient, lower), thus causing mRNA repression and (partial) cell inhibition. TCR, T-cell receptor; EVs, extracellular vesicles. References Ananieva E. A., Patel C. H., Drake C. H., Powell J. D., Hutson S. M. (2014). Cytosolic branched chain aminotransferase (BCATc) regulates mTORC1 signaling and glycolytic metabolism in CD4+ T cells. J. Biol. Chem. 289 18793–18804. 10.1074/jbc.M114.554113 - DOI - PMC - PubMed Bartel D. P. (2018). Metazoan MicroRNAs. Cell 173 20–51. 10.1016/j.cell.2018.03.006 - DOI - PMC - PubMed Batista A., Millan J., Mittelbrunn M., Sanchez-Madrid F., Alonso M. A. (2004). Recruitment of transferrin receptor to immunological synapse in response to TCR engagement. J. Immunol. 172 6709–6714. 10.4049/jimmunol.172.11.6709 - DOI - PubMed Bluestone J. A., Mackay C. R., O’Shea J. J., Stockinger B. (2009). The functional plasticity of T cell subsets. Nat. Rev. Immunol. 9 811–816. 10.1038/nri2654 - DOI - PMC - PubMed Bronevetsky Y., Villarino A. V., Eisley C. J., Barbeau R., Barczak A. J., Heinz G. A., et al. (2013). T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire. J. Exp. Med. 210 417–432. 10.1084/jem.20111717 - DOI - PMC - PubMed Show all 45 references

参考サイト PubMed: exsome



バイオクイックニュース日本語版:エクソソーム特集

ゲスト 731人 と メンバー 5人 がオンラインです