Extracellular RNAs: A Secret Arm of Immune System Regulation

Abstract

The immune system has evolved to protect multicellular organisms from the attack of a variety of pathogens. To exert this function efficiently, the system has developed the capacity to coordinate the function of different cell types and the ability to down-modulate the response when the foreign attack is over. For decades, immunologists believed that these two characteristics were primarily related to cytokine/chemokine-based communication and cell-to-cell direct contact. More recently, it has been shown that immune cells also communicate by transferring regulatory RNAs, microRNAs in particular, from one cell to the other. Several studies have suggested a functional role of extracellular regulatory RNAs in cell-to-cell communication in different cellular contexts. This minireview focuses on the potential role of extracellular RNA transfer in the regulation of adaptive immune response, also contextualizing it in a broader field of what is known of cell-free RNAs in communication among different organisms in the evolutionary scale.

Keywords: Cell-free RNAs; RNA; T cells; Treg cells; cellular immune response; extracellular vesicles; immune system; lymphocyte; nucleic acid.

FIGURE 1.

Examples of EV-associated miRNAs relevant in the cross talk of immune cells. a, both B and T lymphocytes release EV-associated miR-150, which increases significantly in blood upon immune system activation. b, dendritic cell-derived miR-155 enhances whereas miR-146a reduces inflammatory response. c, mature macrophages release EV-associated miR-223, which induces the differentiation of recruited monocytes. d, regulatory T cells release Let-7d, which affects Th1 cells, halting their proliferation and IFNγ secretion. Whether EV-associated miRNAs functioning at a paracrine level may also be released in the bloodstream and which cells would be targeted is still largely unknown. Abbreviations: T = T cells; B = B cells; DC = dendritic cells; MC = monocytes; Mφ = macrophage.