microRNAs and immune response

A specific type of microRNA, miR-181a, plays an important role in controlling T cell responsiveness to antigens by regulating the T cell receptor signalling pathway, a new study has found.

Because the T cell response to antigens is one of the primary components of certain autoimmune disorders, these findings further validate miRNAs as disease targets and point to new potential therapeutic applications for antagomirs, a novel class of oligonucleotide-based inhibitors of specific miRNAs.

RNAi therapeutics company Alnylam Pharmaceuticals announced publication of the pre-clinical study in the journal Cell, in conjunction with Stanford University.

"Our research points to a critical role for miRNAs, specifically miR-181a, in the regulation of T cell biology," senior author Dr Mark Davis, of Stanford University School of Medicine, said.

"We're excited about this new discovery as it represents the first clear example of a role for miRNAs in the immune response to antigens."

Upward or downward modulation of miR-181a was found to control certain aspects of T cell development and to regulate T cell responses to antigens via the T cell receptor signaling pathway, the study found.

"Alnylam's research on miRNAs derives from our discovery of antagomirs, a novel class of oligonucleotide inhibitors of miRNAs," Alnylam's VP for drug discover, Dr Muthiah Manoharan, said. "These reagents have become powerful tools to investigate the role of miRNAs in biology and disease processes."

T cells play a central and coordinating role in cell-mediated and acquired immunity. Recognition of both self and foreign molecules by T cells occurs through activation of the T cell receptor. Activation of T cells through the T cell receptor involves the complex regulation of multiple biological pathways inside the cell.

miRNAs are a broad class of small RNAs that have been shown to regulate the expression of a large number of genes in the human genome through the RNAi pathway, and many of these miRNAs are believed to be involved in disease processes. Certain miRNAs, including miR-181a, are known to play a role in B and T cell development, but their function in antigen recognition is poorly understood.

In the current study, increasing expression of miR-181a was found to increase T cell sensitivity to antigens, while inhibiting miR-181a was found to decrease the immune response. miR-181a was found to regulate the responsiveness of the T cell receptor to antigens by the coordinated down-regulation of a set of phosphatase genes.

Inhibiting miR-181a function with a selective antagomir, antagomir-181a, resulted in efficient reduction in T cell receptor sensitivity to antigens. Since abnormal T cell activity toward self antigens underscores the pathology in many autoimmune disorders, antagomirs selective for miR-181a could define a future therapeutic strategy for the treatment of these diseases.

Source: Alnylam Pharmaceuticals