T cell antigen receptor (TCR) signals can help control the development, activation, and survival of T cells by involving multiple layers and mechanisms regulated by a variety of genes. M6-methyladenosine (m6A) is one of the most common messenger RNA molecular modifications, which can affect transcript splicing, translation, and stability. Scientists from the University of Munich and other institutions revealed the vital function of M6A modification in T cells in a study titled “The function of Wtap in N6-adenosine methylation of mRNAs controls T cell receptor signaling and survival of T cells” published in the international journal Nature Immunology.
Methylation is a chemical modification of nucleic acid that occurs on DNA and RNA molecules. The researchers do not fully understand the significance of this alteration for a particular cell type and how it affects the connection between the body and cells. The most abundant mRNA modification is M6A, which seems to play a crucial role in cell differentiation and biological processes. The researchers found that a methyl group is adsorbed on the sixth carbon atom of nuclear adenosine in M6A, and the researchers found that the so-called “writer complex” may be responsible for this, as it determines which mRNA adenosine is modified to carry new information outside the genetic code, which is read by so-called reading proteins. The latter can determine the lifespan of the mRNA or translate it into the encoded protein.
In this paper, the researchers investigated how the deletion of M6A affects the biological characteristics of T cells. For this reason, the researchers knocked out a component of the M6A writer complex in mice, including regulatory T cells and primitive T cells. Previous studies have shown that M6A modification is essential for T cell function when antigens are recognized. Antigen recognition will lead to T cell activation, cell division, and the acquisition of effector function. Regulatory T cells lacking M6A can not control the immune response. On the other hand, primordial T cells will be blocked and fall into a “coma” during differentiation.
The latest findings suggest that primitive T cells may be different and genetic inactivation regulated by the M6A gene may alter T cell signal transduction and increase calcium flow, making them overactive and inducing cell death. The absence of m6A regulation in T cells may make mice cause severe inflammation, suffering from colitis. This disease is usually induced by the over-activation of conventional T cells because regulatory T cells can no longer slow down the activation of primordial T cells. Complex disorders of immune response will occur in T cells lacking M6A, and primordial T cells activated by antigen recognition will begin to divide and then die, resulting in illnesses caused by the loss of regulatory T cell inhibition.
Next, the researchers want to continue to study special molecules that recognize this methylation modification. They want to identify new key molecules activated by T cells through an in-depth understanding of this type of genetic regulation, so that they can understand which mRNAs will be modified, thus requiring a precise definition of the level of an immune response without error. Researchers may know which nodes can apply in therapy after fully understanding how this regulation prevents cell death or overactivation, researchers may know which nodes can be therapeutically manipulated. In summary, the study reveals how m6A modification affects T cell antigen receptor signaling and determines the mechanism of T cell activation and survival.