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How Tiny Changes Help T Cells to Survive

New Research Findings, Molecular Targets and Therapeutics, AMIR,

Researchers gain a fundamental insight for epitranscriptomics and immune response. The research group around Vigo Heissmeyer and Taku Ito-Kureha of Helmholtz Munich and Ludwig-Maximilians-Universität München has revealed the essential function of m6A modifications in T cells.

The Research Unit Molecular Immune Regulation (AMIR) at Helmholtz Munich focuses on the molecular mechanisms of gene regulation in T cells. „We study the gene regulation that takes place when the mRNA is made and is then translated into a protein. The transcript is our focus. We are investigating the way in which, after transcription has taken place, it is decided how much protein is made from the messenger molecule. And how this process can be controlled. This is because it makes a decisive contribution to various immune responses“, Vigo Heissmeyer, Professor for Immunology and Head of the Research Unit at Helmholtz Munich says.

The mRNA methylation m6A
It has been known for decades that a chemical modification of nucleic acids, methylation, exists not only on DNA but also on RNA. But the fact that methylation also has a function there was discovered by scientists only a few years ago. This gave rise to the research area of epitranscriptomics. The focus here is on investigating the regulatory potential of mRNA methylation. Whether this methylation is important for certain cell types and what effects it has on the interaction of cells in the body is still unclear according to current knowledge.
The most abundant mRNA modification is N6-methyladenosine (also called m6A). It appears to play a crucial role in cell differentiation and to influence a number of biological processes. In m6A, a methyl group is attached to the sixth carbon atom of the nucleic base adenosine. Researchers found that a so-called writer complex is responsible for this - as in DNA. It decides which adenosine in which mRNA is modified and thus carries new information in addition to the genetic code. This information is then "read" by so-called reader proteins, which then decide on the lifetime or translation of the mRNA into the encoded protein.

New success for basic research

Vigo Heissmeyer and his research team investigated how the loss of m6A affects the biology of T cells. To this end, the scientists knocked out a component of the m6A writer complex in mice in their study - both in regulatory T cells and naive T cells. From former studies, the researchers deduced that m6A modifications are essential for T cells when they recognize an antigen. Normally, antigen recognition would lead to T cell activation, cell division and acquisition of effector function. Regulatory T cells without m6A would lose control over the immune response. Naive cells, on the other hand, would stop in their development and fall into a kind of coma - that was the state of research.
But the new study shows something different for naive T cells: Genetic inactivation of m6A gene regulation is associated with stronger and more sustained Ca2+ signaling after antigen receptor activation. Previous work suggests that naive T cells use m6A to regulate cytokine signaling in the activation process. As the researchers now found, T cells lacking m6A can still be activated by cytokines. After antigen recognition, however, only a few of these T cells can divide, as most undergo activation-induced cell death (AICD) and then disappear (see Figure 2).

Surprisingly, the T cells without m6A modifications even show hyperactivity. This change is explained by m6A-dependent regulation of the ORAI1-Ca2+ channel, which, together with RIPK1 kinase, also m6A-dependently regulated, is involved in the observed sudden death of T cells. The lack of regulation in T cells due to the loss of adenosine methylation shows a severe inflammatory response in mice. They suffer from colitis, the chronic inflammation of the intestine. This disease is triggered by an excess of activated conventional T cells. An imbalance emerges because the regulatory T cells can no longer dampen activation of the naive ones. In the absence of m6A in T cells, a complex deregulation of the immune response occurs, naïve T cells that are activated by antigen recognition, divide initially, but also die increasingly - and can still cause the disease, presumably due to lack of suppression by regulatory T cells.

What future research can be derived from these findings?

A next step will be to study the molecules that recognize methylation. „Our idea is to identify new key molecules through insights into gene regulation. We can see from our study which mRNAs are modified and thus need to be precisely defined in quantity for immune responses to be error-free. If we fully understand how this regulation prevents cell death or hyperactivation, we will also know which nodes can be therapeutically manipulated“, Vigo Heissmeyer explains. For this purpose, the team has created a map, which each researcher can take from the publication. (Example see Figure 2). On it, experts find the m6A modifications on the mRNAs of the T-cell transcriptome. Anyone can read off where the methylations are positioned on any gene - or whether they do not exist, whether they are bound by the reader or not. This information can serve as a basis for further investigations and questions.

Relevance for practice

The study highlights target mRNAs of post-transcriptional gene regulation that need to be tightly regulated in expression, as even small deviations dramatically alter cell fate. This knowledge can be used, for example, in adoptive T cell therapies, where the survival of T cells in repeated antigen encounters is critical for success.

Original publication

Taku Ito-Kureha et al., 2022: The function of Wtap in N6-adenosine methylation of mRNAs controls T cell receptor signaling and survival of T cells. Nature Immunology. DOI: <link - extern>10.1038/s41590-022-01268-1</link>


* Figure 1 - T-cell receptor-dependent cell division
(© Nature Immunology / Vigo Heissmeyer)
Experiment in which T cells are transferred into mice that themselves have no T and B cells at all.
(Left) Image of transfer of T cells from a wild-type mouse with m6A: High cell division activity (cells with low CTV signal) is detected in T cells after recognition of gut bacteria antigens (TCR-dependent). The cytokine IL-7 leads to low cell division, which occurs slowly but in all cells. (Right) Image of the transfer of T cells from the knockout mouse without m6A: Small peak of T cells in the cell division pattern characteristic of stimulation by the T cell receptor. More cells respond to IL-7. This result suggests that T cells can divide as rapidly but then disappear, as demonstrated with further experiments.

** Figure 2 - Map of m6A modifications in the mRNA of the gene "Orai1"
(© Nature Immunology / Vigo Heissmeyer)
The top row shows how the writer positions methylation m6A on Orai1 mRNA. Methylation is characterized by mountains with steep slopes to areas of missing label. The row below shows a reader that was the focus of the study. It binds most strongly where m6A is positioned. Below that, the break-off edges in overlapping areas are summarized as bars.