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New Study Finds miR-155 Controls CD8+ T Cells Via Interferon Regulation


A new study has identified a link between microRNA-155 and the immune system, showing that the small, non-coding RNA plays a key part in mediating the activity of CD8+ T cells against pathogens.

The findings, which appeared this week in Nature Immunology, pinpoints a previously unknown function for miR-155, and indicates that the miRNA controls the CD8+ T cells by regulating interferon signaling.

CD8+ T cells are a critical part of the adaptive immune system, providing immunity to a host of intracellular pathogens and malignant cells. Meanwhile, miRNAs have been shown to be important players in immunity, with studies showing impairment of CD4+ T cells lacking Dicer, for instance.

“However, the role of individual microRNAs in the CD8+ T cells response is largely unexplored,” the team wrote in Nature Immunology.

Looking to address this, the investigators focused their attention on miR-155 in light of earlier research establishing it as critical for the function of B and T lymphocytes and dendritic cells, while finding a “wide spectrum” of gene targets in CD4+ T cells, according to senior author and Babraham Institute researcher Martin Turner. The miRNA had also been previously implicated in B cell differentiation.

They began by looking at the effect the status of CD8+ T cells had on miR-155, and found that after in vitro stimulation, naive CD8+ T cells rapidly increased their expression of the miRNA. Further, miR-155 expression was significantly increased in CD8+ T cells isolated from the lungs of mice infected with influenza, all of which implicated the miRNA in regulating the T cells’ responses.

To extend their observations, the team then infected miR-155-deficient and wild-type mice with a sublethal dose of influenza. The miR-155-deficient mice showed a “much lower frequency and number” of lung-specific CD8+ T cells, as well as impaired viral clearance, versus their normal counterparts.

The researchers also examined whether miR-155 deficiency impacted CD8+ T cell responses to bacterial infection. In mice lacking the miRNA, CD8+ T cell levels were 15 times lower in response to Listeria monocytogenes infection than in control animals.

In addition to diminished primary CD8+ T cell responses, miR-155-deficient mice had significantly fewer memory cells versus their wild-type counterparts

“When we analyzed short-lived effector cells and memory precursor effector cells during the primary response, we found that miR-155 deficiency impaired the abundance of each population,” the researchers wrote. “These findings indicated that miR-155 was required for the establishment of a CD8+ T cell memory pool during pathogenic infection.”

Overall, miR-155 appears to have an “intrinsic role” in regulating primary CD8+ T cell responses to pathogens and affects establishment of memory CD8+ T cells, they added.

Having shown that miR-155 deficiency negatively affects CD8+ T cell responses, the investigators examined whether its overexpression would enhance immunity.

Indeed, in mice transduced with CD8+ T cells with a vector expressing miR-155 and infected with influenza, pulmonary CD8+ T cell populations expanded five times more than in infected animals transduced with a control vector. Mice receiving the miR-155 vector also had lower viral loads.

Through their work, the investigators also addressed an “unresolved paradox” concerning the role of type I interferon signaling in CD8+ T cells as a “critical costimulatory signal,” which contrasts its well-known antiproliferative effects, according to the Nature Immunology paper.

“It was already known that the interferon signaling pathway could inhibit the activation of CD8+ T cells,” Turner told Gene Silencing News, but the mechanism behind this is poorly understood. “We were thinking … [that] maybe the microRNA is involved in dampening or inhibiting that pathway.”

Gene-expression profiling conducted by the researchers showed that miR-155-deficient CD8+ T cells had enhanced type I interferon signaling and were more susceptible to interferon’s antiproliferative effect.

They also found that inhibiting the type I interferon-associated transcription factor STAT1 triggered enhanced responses of miR-155-deficient CD8+ T cells in vivo, suggesting that the miRNA may influence changes in responsiveness to type I interferon by acting on the STAT1 signaling pathway.

“The amount of miR-155 may also function as a key modulator of CD8+ T cell responses in the presence of type I interferons, determining whether type I interferons act as costimulatory signals or as inhibitors,” the team wrote.

Turner noted that in other cell types where miR-155 has “important biological consequences for cell function,” it appears that the miRNA does not affect the type I interferon pathway.

“It may be that microRNA-155 targets different pathways in a cell type-specific way to modulate the function of different cells,” he said.

“It seems clear that microRNA targets are context-dependent,” he added. “I think that’s quite an interesting idea.”