Immune Regulator miRNA-142 Could Advance Cancer, Autoimmune Disease Research

A new study has identified a critical regulator of immunity, called microRNA-142, which could have significant implications for understanding or even treating autoimmune diseases and cancer.

The study, “microRNA-142-mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance,” was published in The Journal of Clinical Investigation.

The body’s immune system has a tricky job. On one hand, it needs to recognize and attack anything that might cause a disease, whether it’s an invading bacteria or a person’s own cells that are behaving abnormally, such as cancer cells. On the other hand, the immune system isn’t supposed to target the body’s normal, healthy cells, which leads to autoimmune diseases such as lupus.

One of the ways the immune system attempts to keep this balance is through regulatory T-cells (Tregs). Tregs are able to suppress other immune cells, like effector T-cells, which do a lot of the actual fighting in the immune system. In this way, Tregs can prevent other immune cells from attacking when they shouldn’t.

As their names suggest, effector and regulatory T-cells have a lot in common biologically, even though they serve essentially opposite functions. Further understanding of exactly which molecular and/or genetic changes in these cells affect their function, as well as uncovering how such changes occur, could have implications for how we understand and treat a variety of diseases, from autoimmunity to cancer.

The researchers who published this study were particularly interested in how Tregs are affected by microRNAs (miRNAs), small RNA molecules that can help regulate how and whether other genes are expressed in cells.

To do this, they determined whether any miRNAs in mouse Tregs were activated by FOXP3 — a “master regulator” that essentially makes cells become Tregs. They found that miRNA-142 was significantly activated by FOXP3, suggesting that this miRNA plays a role in Treg development.

The researchers further determined that miRNA-142 acts by decreasing the level of the protein phosphodiesterase 3B. Phosphodiesterase 3B, in turn, can decrease the amount of cyclic AMP (cAMP) in cells, and Tregs need high cAMP levels to function. So, miRNA-142 ultimately helps to drive Treg development by increasing cAMP levels.

Researchers then examined what happened when miRNA-142 was deleted from Treg cells of mice. They found that these mice spontaneously developed systemic, lethal autoimmune reactions, supporting the role that this miRNA plays in getting Tregs to do their jobs.

Pharmacological targeting of phosphodiesterase 3B in these mice — essentially mimicking the function of miRNA-142 with a drug — could prevent this autoimmunity, further supporting the biological importance of this newly discovered regulatory system.

“These findings represent a significant step forward in the understanding of the immune system and we believe many people worldwide may benefit,” Graham Lord, one of the researchers, said in a press release.

Further research will be needed to confirm whether this pathway works the same way in humans — though the researchers point out in their paper that the miRNA-142 gene is fairly well-conserved, so it’s likely.

Additionally, the investigators said, “this mechanism may prove a future avenue for Treg-targeted immunotherapies for autoimmune disease and solid tumors as well as for augmenting the response to pathogens.”