The immune system not only responds to infections and other potentially problematic abnormalities in the body, it also contains a built-in brake in the form of regulatory T cells. These cells ensure that inflammatory responses don’t get out of hand and do damage. In autoimmune diseases, sometimes T cells don’t act as they should. Now, a new study led by researchers at the University of Pennsylvania has demonstrated how T cells can themselves be regulated hydrogen sulfide, a gas produced by the body’s muscle cells and one often associated with the smell of rotten eggs. The team state that the finding unveils several new possible points for therapeutic intervention, with implications for autoimmune diseases as well as other conditions such as cancer and hypertension. The opensource study is published in the journal Immunity.
Previously researchers have thought of signaling pathways as entailing a ligand binding to a receptor. However, gases can also trigger signaling cascades in the body. The best known is nitric oxide, or NO, which regulates a host of functions, notably blood pressure. Carbon monoxide is another so-called ‘gasotransmitter.’ Though less is known about it, researchers have also come to understand that hydrogen sulfide gas plays a suite of important roles in the body as well. Reduced levels of H2S have been associated with immune disorders, cancer and hypertension. It has also been shown that high levels of it are toxic, however, the human body maintains it at a certain level and cells produce it.
In an earlier study from the team results showed that mesenchymal stem cells produce and rely on H2S for proper functioning. In the course of that study, they noticed that mice with reduced levels of H2S had problems consistent with autoimmune disease. To see if they could pinpoint the role of the gas in immune regulation, the researchers examined T cells in culture and found that they, too, produce H2S. Mice bred to produce reduced levels of H2S had abnormally low numbers of T cells and, as a result, developed autoimmune disease that affected multiple organs. Giving these mice compounds that release H2S partially alleviated these effects, and the animals lived longer.
Next, the lab wanted to find out more about the mechanism by which H2S acted on the immune system. They had already observed that H2S-deficient T cells had lower levels of a T cell marker called Foxp3, however, H2S did not seem to affect the actors of a known pathway by which Foxp3 is produced. So the group hypothesized that H2S might act in another, as-yet-uncharacterized pathway to regulate Foxp3 expression.
The current study began to map the pathway. The data findings showed that mice with reduced H2S production had large numbers of methyl groups on the Foxp3 gene, tags which repress the gene’s expression. It was already known that demethylation of Foxp3 can occur through two enzymes called Tet1 and Tet2. However, the results revealed that H2S regulates the expression of Tet1 and Tet2 by modifying a transcription factor called NFYB by adding a sulfur atom to it, a process called sulfhydration.
The team showed that reducing H2S levels led to reduced expression of Tet1 and Tet2 in T cells and, consequently, impaired function and development of T cells. The findings proved that they could partially reverse these effects by adding back a source of H2S. The group state that to their knowledge this is the first time anyone has connected sulfhydration with Tet and Tet with Foxp3. The lab conclude that it’s becoming clear that H2S has a very important role to play in immune regulation.
For the future the team are continuing to examine how H2S operates in the context of both stem cells and T cells and are looking, too, to see whether it plays critical roles in other cell types. They are also following up on the current work to identify ways to intervene when H2S levels fall in order to prevent autoimmune problems.
Source: University of Pennsylvania
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
Michelle has been picked up as an expert writer for Informa publisher’s Clinical Trials community, as well as being listed as a blog source by the world’s leading medical journals, including the acclaimed Nature-Springer journal series.
Healthinnovations is currently indexed by the trusted Altmetric and PlumX metrics systems, respectively, as a blog source for published research globally. Healthinnovations is also featured in the world-renowned BioPortfolio, BioPortfolio.com, the life science, pharmaceutical and healthcare portal.
Most recently the Texas A&M University covered The Top 10 Healthinnovations series on their site with distinguished Professor Stephen Maren calling the inclusion of himself and his team on the list a reflection of “the hard work and dedication of my students and trainees”.
Michelle Petersen’s copy was used in the highly successful marketing campaign for the mega-hit film ‘Jumanji: The Next Level, starring Jack Black, Karen Gilian, Kevin Hart and Dwayne ‘The Rock’ Johnson. Michelle Petersen’s copywriting was part of the film’s coverage by the Republic TV network. Republic TV is the most-watched English language TV channel in India since its inception in 2017.
An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.