Immunity system complexity: RNA guides T cells (Introduction)

by David Turell , Tuesday, April 02, 2024, 17:55 (27 days ago) @ David Turell

RNA outside on cell surfaces call for T cell actions:

https://www.the-scientist.com/cell-surface-rna-helps-neutrophils-get-around-71758?utm_c...

"...when RNA molecules were detected on the surface of several cell types, researchers wondered what purpose they might serve. A recent study has revealed one of their functions: mobilizing immune cells to inflamed tissue.

"Published last month in Cell, a Yale University team led by geneticist Jun Lu and pharmacologist Dianqing Wu described how cell surface RNA helps neutrophils latch onto endothelial cells and infiltrate tissue. Removing the molecules prevents the immune cells from reaching inflammatory sites in mice, highlighting their role in the immune system’s response to potential threats.

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"Proof of cell-surface RNAs first came to light in 2020, when they were detected on immune cells in human blood.2 The following year, Bertozzi’s group found the molecules littering the surface of cancer cells and stem cells, where they are welded to a sugar chain.3 Like glycoproteins and glycolipids, this new category of molecule, christened glycoRNAs, appeared to bind to immune receptors, pointing to potential immunoregulatory functions.

"When Lu came across these papers, he responded with a healthy dose of skepticism. After all, he reasoned that any exposed RNA should be torn apart by RNases, RNA-degrading enzymes that roam the blood plasma.

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"His team began by using a chemical marker called biotin to label any sugar chains present on the neutrophil surface, tagging glycoproteins, glycolipids, and—potentially—glycoRNAs. Without rupturing the cell membrane, they purified RNA from labeled cells and then applied RNase at concentrations far higher than typically found in the human body. If the enzyme diminished the biotin signal, some sugars on the cells must be bound to extracellular RNA. To Lu’s surprise, the signal vanished, confirming the presence of glycoRNAs on the cell surface.

"If glycoRNAs share similar functions to glycoproteins and glycolipids, they may help immune cells reach inflammatory sites. To test this, the researchers dyed some neutrophils red and degraded their extracellular glycoRNAs using RNase. They labeled other neutrophils green but left their surface RNAs intact. After injecting the dyed cells into a mouse that had abdominal inflammation, Lu’s team found that the cells lacking glycoRNAs were less likely to reach the stomach.

"To infiltrate tissue, neutrophils must first latch onto exterior cells and then traverse through several cell layers. Lu wondered whether glycoRNAs contributed to both stages of this process, so his team placed neutrophils on one side of a cultured endothelial layer and a chemoattractant on the other. Immune cells lacking glycoRNAs showed less adhesion and reduced migration through the cell layer in vitro. Without the endothelial barrier, the cells migrated normally, suggesting that glycoRNAs do not affect cell mobility.

"To uncover how neutrophil glycoRNAs mediate attachment to endothelial cells, the researchers split the molecule into its sugar and RNA components. Saturating the same cell culture system with glycans blocked the immune cells from migrating through the endothelial layer, while RNA saturation had no effect. The findings suggested that—in a similar manner to other glycoconjugates—the glycan portion latches onto endothelial cells, while the RNA tethers the sugar to the membrane.

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"After culturing the cells together for three days, the team detected the chemical tags on only green cells, suggesting that the RNA is produced in-house rather than transferred from the external environment.

"Sequencing the glycoRNA molecules turned up hits for ribosomal RNA, transfer RNA, and small nucleolar RNAs, suggesting that they may be repurposed fragments of noncoding nucleic acids. Yet the rules that determine which bits of RNA end up on the membrane, and how they are protected from degradation, are unclear."

Comment: T cells need to be guided to spots requiring inflammation. That RNA's are freely acting as chaperons is an amazing finding. The group of various RNAs are truly the workhorses of the genome. DNA is an inert code until activated by RNA actions.