Transfer of extracellular vesicle‐microRNA controls germinal center reaction and antibody production

• Published in: EMBO reports Vol. 21; no. 4; pp. e48925 - n/a
• Main Authors: Fernández‐Messina, Lola, Rodríguez‐Galán, Ana, de Yébenes, Virginia G, Gutiérrez‐Vázquez, Cristina, Tenreiro, Sandra, Seabra, Miguel C, Ramiro, Almudena R, Sánchez‐Madrid, Francisco
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.04.2020; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Animals; Antibodies; Antibody Formation; antibody production; Apoptosis; BIM protein; Cell Communication; Cell cycle; Cell interactions; Cell signaling; Cell survival; Chimeras; Class switching; Defects; Disorders; EMBO19; EMBO20; EMBO36; exosomes; Extracellular Vesicles; Gene expression; Germinal Center; germinal center (GC) reaction; Germinal centers; Griscelli syndrome; Inflammatory diseases; Lymphocytes; Lymphocytes B; Lymphocytes T; Mice; MicroRNAs; MicroRNAs - genetics; miRNA; Mutation; Pathogenesis; PTEN protein; Ribonucleic acid; RNA; Survival; Switching; Vesicles; microRNAs; antibody production; extracellular vesicles; germinal center (GC) reaction; exosomes
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201948925

Intercellular communication orchestrates effective immune responses against disease‐causing agents. Extracellular vesicles (EVs) are potent mediators of cell–cell communication. EVs carry bioactive molecules, including microRNAs, which modulate gene expression and function in the recipient cell. Here, we show that formation of cognate primary T‐B lymphocyte immune contacts promotes transfer of a very restricted set of T‐cell EV‐microRNAs (mmu‐miR20‐a‐5p, mmu‐miR‐25‐3p, and mmu‐miR‐155‐3p) to the B cell. Transferred EV‐microRNAs target key genes that control B‐cell function, including pro‐apoptotic BIM and the cell cycle regulator PTEN. EV‐microRNAs transferred during T‐B cognate interactions also promote survival, proliferation, and antibody class switching. Using mouse chimeras with Rab27KO EV‐deficient T cells, we demonstrate that the transfer of small EVs is required for germinal center reaction and antibody production in vivo, revealing a mechanism that controls B‐cell responses via the transfer of EV‐microRNAs of T‐cell origin. These findings also provide mechanistic insight into the Griscelli syndrome, associated with a mutation in the Rab27a gene, and might explain antibody defects observed in this pathogenesis and other immune‐related and inflammatory disorders. Synopsis Immune synapse formation promotes the transfer of specific microRNAs via extracellular vesicles from T to B cells, regulating the germinal center reaction and antibody production. These findings might explain antibody defects observed in Griscelli syndrome and other immune‐related disorders. A restricted set of T‐cell‐derived EV‐microRNAs are found in B cells upon immune synapsis. Transferred EV‐microRNAs modulate B cell targets involved in survival, proliferation and antibody class switching. T‐cell‐derived EV‐microRNAs control the germinal center reaction and antibody production in vivo . Graphical Abstract Immune synapse formation promotes the transfer of specific microRNAs via extracellular vesicles from T to B cells, regulating the germinal center reaction and antibody production. These findings might explain antibody defects observed in Griscelli syndrome and other immune‐related disorders.