New Discovery Reveals How ‘Sentinel’ Immune Cells Are Maintained
WEHI researchers have made a surprising discovery about how immune “sentinel” cells are maintained, which could have implications for drugs in development for treating cancer.
Researchers studied the impact of removing specific proteins in immune cells that were responsible for controlling the ability of cells to silence or turn off genes.
They were surprised to find that a population of “sentinel” immune cells were affected by the removal of a component from the machinery, causing the skin and lung cells to completely disappear. This suggests that drugs that inhibit this component to treat diseases, such as cancer, could have unexpected consequences for the immune system.
The research was led by Dr Yifan Zhan, Dr Yuxia Zhang, Mr Shengbo Zhang, Dr Michael Chopin, Professor Stephen Nutt and colleagues, and has been published in Scientific immunology.
In one look
- WEHI scientists found that interfering with cellular components that regulate gene expression had unexpected and contrasting effects on immune sentinel cells.
- Although they were surprised to find that immune cells were largely unaffected, removing a component of the complex caused sentinel cell populations to completely disappear from the surface of the body, such as skin and lungs.
- The findings could have ramifications for the development of drugs that target these complexes to treat cancers and other diseases.
A complex problem
The research team studied the role of the repressive polycomb 2 complex (PRC2) in first-line immune cells.
Dr Chopin said PRC2 was responsible for “turning off” genes, including in immune cells, which was essential to maintain their numbers and normal function.
Our lab studies the regulation of genes, or the molecular processes inside cells that control how and when the genes encoded by our DNA are used.
We have studied the function of PRC2 in two populations of immune cells that form the first line of defense against infection. These cells provide a critical immune barrier to the external environment, protecting the skin and lungs from microbial invasion. “
Dr Michel Chopin
The research team removed two components of the complex, an enzyme called EZH2 and a structural protein called Suz12, to see its impact on the development, populations and function of immune cells.
Suppression of EZH2 had no impact on the biology or function of either cell population, as the cells were still able to respond effectively to viral infection.
“We were surprised to find that immune cells were largely unaffected by the suppression of EZH2,” said Dr Chopin.
On the other hand, when Suz12 was removed, some populations of macrophages, such as those that reside in our skin and lungs, were completely gone.
“These tissue-residing macrophages are responsible for detecting and ridding the body of a variety of infiltrating bacteria and virus-infected cells, and alerting the body that it is under attack by stimulating the production of inflammatory signals.” said Dr Chopin.
“Tissue-resident macrophages have the unique property of being able to independently maintain their numbers throughout adult life. Our research demonstrates a key role for Suz12 and PRC2 in controlling this regulatory program of these immune cells. “
Prof Nutt said it’s important to understand the potential knock-on effects of drugs that interfere with proteins that turn off genes.
“PRC2 has been implicated in many cancers, such as lymphoma. Significant work is being done around the world to develop drugs that target components of the complex to treat cancer.
He said at least one drug already approved for the treatment of a rare type of sarcoma inhibits components of the complex.
“We need to study more closely whether drugs that inhibit the function of EZH2 and Suz12 could have unintended consequences for the immune system,” he said.
On the flip side, Professor Nutt said, it was also important to understand what redundancies exist that could prevent the drugs from having the desired effect.
“The current belief is that inhibiting EZH2 will dampen the immune response, for example if you want to treat immune or inflammatory diseases,” Professor Nutt said. “Our research shows that, at least with these specific first-line immune cells, which are active early in infection and trigger other parts of the immune system, this is unlikely to be the case.”
Prof Nutt said the research was part of the team’s larger focus on gene regulation at the molecular level.
“The normal function of cells in our body depends on the ability of each cell to use the right combination of genes from the tens of thousands of genes encoded in our DNA in the right place at the right time,” he said.
“The molecular controls that prevent genes from being used are essential to life.”
The research was supported by the Australian National Council for Health and Medical Research, WEHI Innovation Grant and the Government of Victoria.
Walter and Eliza Hall Institute
Zhan, Y., et al. (2021) Differential requirement for Polycomb Repressor Complex 2 in dendritic cells and tissue-resident myeloid cells. Scientific immunology. doi.org/10.1126/sciimmunol.abf7268.