Skip to main content
Premium Trial:

Request an Annual Quote

Study Backs Theory That miRNAs Can Discern Antigens; Others May Regulate Cardiac Stress

Premium
Researchers from Stanford University and Alnylam Pharmaceuticals last week showed that a single microRNA can play an important role in helping T cells recognize antigens.
 
Separately last week, researchers from the University of Texas Southwestern Medical Center showed that a heart-specific miRNA can help control stress-dependent cardiac growth and gene expression.
 
The T cell research, which was published last week in the online edition of Cell, shows that the miRNA miR-181a appears to act as a rheostat that can control how T cells respond to antigens by regulating the T-cell receptor-signaling pathway, Alnylam said.
 
The investigators also reported that they were able to use Alnylam’s antagomirs, single stranded RNA analogues complementary to a specific miRNA, to silence miR-181a, thereby reducing T-cell receptor (TCR) sensitivity to antigens.
 
According to the company, the findings “further validate miRNAs as disease targets and point to new potential therapeutic applications for antagomirs.”
 
I, T Cell
 
“One of the key features of a functioning immune system is its ability to distinguish antigens of foreign origin from those derived endogenously, and to mount an immune response against the former,” the authors wrote in Cell. “With respect to T cells, this goal is achieved through antigen recognition by T cell receptors and a highly ordered developmental process in the thymus.”
 
Research indicates that a T cell’s responsiveness varies with the cell’s different developmental stages, suggesting that “T cell sensitivity is intrinsically regulated during maturation … to ensure proper development of specificity and sensitivity to foreign antigens while avoiding self recognition,” they added. “But how this is accomplished remains elusive.”
 
To shed some light on this process, the Stanford and Alnylam researchers decided to study miR-181a, an miRNA previously shown to have a role in B and T cell differentiation, and which is strongly expressed in the mouse thymus.
 
Boosting miR-181a expression in mature T cells caused the cells to be more sensitive to peptide antigens, according to the Cell paper. Suppressing the miRNA in immature T cells using antagomirs, meanwhile, reduced the cell’s sensitivity to antigens and impaired both positive and negative selection.
 
“Moreover, quantitative regulation of T cell sensitivity by miR-181a enables mature T cells to recognize antagonists — the inhibitory peptide antigens — as agonists,” the researchers wrote. “These effects are in part achieved by the down-regulation of multiple phosphatases, which leads to elevated steady-state levels of phosphorylated intermediates and a reduction of the T cell receptor signaling threshold.”
 
The researchers also noted that higher levels of miR-181a expression correlated to greater T cell sensitivity in the immature cells, “suggesting that miR-181a acts as an intrinsic antigen-sensitivity rheostat during T cell development.”
 
However, the pointed out that their findings do not “exclude the possibility that other TCR signaling components or other miRNAs may also contribute to changes in [T cell] sensitivity.”

Additionally, miR-181a is “also likely to have other roles in T cell function since it also influences the co-stimulatory pathway through as yet unknown targets,” they wrote. “Collectively, our findings suggest that miRNAs may be evolutionarily selected gene-regulatory molecules that can carry out integrated biological functions by regulating gene networks posttranscriptionally.”

 
Deep in the Heart
 
Meantime, in Texas, researchers have shown that the heart-specific miRNA miR-208 can help control stress-dependent cardiac growth and gene expression. Their findings appear in last week’s online edition of Science.
 
"We've discovered a new and completely unanticipated mechanism for regulating the contractility of the heart," Eric Olson, senior author of the study, said in a statement. "We're very excited about the therapeutic implications, but we still have much work left to do."
 

"We've discovered a new and completely unanticipated mechanism for regulating the contractility of the heart. We're very excited about the therapeutic implications, but we still have much work left to do."

“Cardiac contractility depends on the expression of two [myosin heavy chain] genes, alpha and beta, which are regulated in an antithetical manner by developmental, physiological, and pathological signals,” according to the authors.
 
Increased beta-MHC expression, they noted, is associated with hypothyroidism and certain forms of cardiac stress, and occurs during cardiac disease when levels of alpha-MHC decrease.
 
“Because even relatively subtle variations in the ratio of alpha- and beta-MHC can profoundly influence cardiac function, there has been great interest in deciphering the mechanisms that coordinate alpha- and beta-MHC expression and in strategies to therapeutically manipulate cardiac MHC expression,” they wrote.
 
Building off previous work examining miRNAs and their role in heart disease (see RNAi News, 11/16/2006), Olson and colleagues looked to miR-208, a highly conserved, miRNA specifically expressed in the heart and encoded by intron 27 of both the human and mouse alpha-MHC gene, for clues to MHC regulation.
 
“To further investigate the potential functions of miR-208, we compared the response of wild-type and miR-208 mutant mice to thoracic aortic banding, which induced cardiac hypertrophy … and is accompanied by down-regulation of alpha-MHC and up-regulation of beta-MHC,” the investigators wrote in Science.
 
In response to the banding, the wild-type mice experienced a significant increase in cardiac mass and hypertrophic growth of cardiomyocytes and ventricular fibrosis. “In contrast, miR-208 mutant animals showed virtually no hypertrophy” in response to the banding.
 
Additionally, the mutants proved to be unable to up-regulate beta-MHC, the researchers wrote. “Instead, alpha-MHC protein expression increased in miR-208 mutant hearts in response [to the banding], which may reflect a compensatory mechanism to maintain MHC expression in the absence of beta-MHC up-regulation.”
 
Based on these and other findings detailed in Science, the results “demonstrate that miR-208 … regulates stress-dependent cardiomyocyte growth and gene expression,” the UT Southwestern researchers wrote.
 
“Therapeutic manipulation of miR-208 expression or interaction with its mRNA targets could potentially enhance cardiac function by suppressing beta-MHC expression,” they added. “Based on the profound influence of miR-208 on the cardiac stress response, and the regulation of numerous miRNAs in the diseased heart, we anticipate that miRNAs will prove to be key regulators of the functions and responses to disease of the adult heart and possibly other organs.”

The Scan

Billions for Antivirals

The US is putting $3.2 billion toward a program to develop antivirals to treat COVID-19 in its early stages, the Wall Street Journal reports.

NFT of the Web

Tim Berners-Lee, who developed the World Wide Web, is auctioning its original source code as a non-fungible token, Reuters reports.

23andMe on the Nasdaq

23andMe's shares rose more than 20 percent following its merger with a special purpose acquisition company, as GenomeWeb has reported.

Science Papers Present GWAS of Brain Structure, System for Controlled Gene Transfer

In Science this week: genome-wide association study ties variants to white matter stricture in the brain, and more.