The Goldilocks mechanism of immune regulation

It appears that regulatory T cells (T_reg) don’t all do as their name suggests.

Researchers at the Walter and Eliza Hall Institute (WEHI) have found that only a subset of T_reg cells actually perform their key function of keeping the immune system in a fine balance.

The finding should shed light on why the immune system over- or under-responds in some situations, and can yield beneficial insights in clinical trials.

It might also be of benefit in treating autoimmune diseases and facilitating organ transplantation.

The WEHI researchers found that with too few T_reg cells, the immune system can run out of control, causing autoimmine disorders. While too many means the immune system is suppressed an can’t respond to pathogens, microbes an cancerous cells.

The WEHI team were trying to determine how T_reg cells perform their function, and discovered that only a subset of the cells are key to regulating the immune system.

"It turns out that the bulk of cells which are classified as regulatory T cells may not do much," said Dr Axel Kallies, a co-author on the study.

"In this study we have identified a distinct group of effector regulatory T cells, or 'active T_regs', which are the key drivers of immune response regulation."

They found that T_reg cells are controlled by a number of transcription factors, including Foxp3.

It’s long been known that mice or humans lacking Foxp3 suffer from severe autoimmune disorders.

But T_reg cells are also controlled by another transcription factor, Blimp-1.

This filled in a previously missing piece of the immune puzzle; it’s been known that mice lacking Blimp-1 suffer from often fatal autoimmune diseases, but it was not known why.

The WEHI team discovered that Blimp-1 differentiates the T_reg cells into a subset that produce an immunomodulatory cytokine, IL-10.

IL-10 specifically regulates the local immune system in areas with mucosal surfaces, such as the lungs and intestines.

This finding has implications for the way clinical trials are assessed, said co-author, Dr Stephen Nutt.

"Researchers often measure regulatory T cell numbers in clinical trials as a parameter for establishing whether there has been a positive immune response," Dr Nutt said.

"We have shown that the absolute number of regulatory T cells isn't as important as the presence of this particular active regulatory T cell population."

Dr Erika Cretney, also a co-author, said that re-defining the active subset of the T_reg population would give researchers the ability to develop new ways to increase or block their activity in the body.

"The next step for my research is to look at the function of this active T_reg population in autoimmunity and in cancer."

Dr Kallies said that for these reasons, there was a lot of excitement in the medical community about regulatory T cells.

"Clinicians have shown that regulatory T cell activity impacts on many therapies," he said. "Many research teams are trying to manipulate and expand these cells for therapeutic use.

“Our finding will transform the way that researchers look at immune responses and open new avenues for treating diseases such as autoimmunity and cancer."

The paper was published in the journal, Nature Immunology.