In the pre-clinical study, a specific miRNA, miR-181a, was shown to play an important role in controlling T cell responsiveness to antigens by regulating the T cell receptor signaling pathway. 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.
“Our research points to a critical role for miRNAs, specifically miR-181a, in the regulation of T cell biology,” said Dr. Mark Davis from Stanford University School of Medicine, a senior author of the publication. “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.”
“In our study, 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,” said Dr. Chang-Zheng Chen, also from Stanford University School of Medicine and a senior author of the publication.
“Alnylam’s research on miRNAs derives from our discovery of antagomirs, a novel class of oligonucleotide inhibitors of miRNAs. These reagents have become powerful tools to investigate the role of miRNAs in biology and disease processes. We are fortunate to collaborate with some of the leading labs across the world, such as our colleagues at Stanford, in our efforts to explore therapeutic opportunities for miRNA antagonists,” said Dr. Muthiah Manoharan, Vice President, Drug Discovery at Alnylam.
“Moreover, this new paper in Cell continues Alnylam’s commitment to scientific excellence and our broad leadership in RNAi research and its translation toward therapeutics,” Dr. Manoharan added.
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 a cell surface receptor called 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.
Recently, Alnylam scientists and collaborators have discovered a new class of oligonucleotide therapeutics, called antagomirs, that inhibit the function of specific miRNAs in vitro and in vivo.
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.