While the immune system is crucial for protecting the body from
infection and disease, prolonged activation can damage healthy tissue.
After its activation, the immune system is shut off by specialized
immune cells known as regulatory T cells (Treg cells). Understanding the
development of Treg cells is thought to be critical for combating
Scientists at the Immunology Frontier Research Center (IFReC), Osaka
University, Japan, report a new molecular mechanism that could explain
the cause of some autoimmune diseases.
‘A new molecular mechanism that could explain the cause of some autoimmune diseases has been reported by scientists.’
"The development of Treg cells in the thymus
depends on super-enhancer establishment," explains IFReC Professor
This super-enhancer establishment permits the expression of genes
specific for Treg cell development. "Super-enhancers appeared to be a
pre-requisite for Treg cell development, so we sought molecules
controlling super-enhancers," he added.
In the most recent publication by the Sakaguchi lab, which can be seen in Nature Immunology,
Sakaguchi and his team report that Satb1 regulates the super enhancers essential for Treg cell development.
Looking at the Treg cell development pathway, the scientists found
that the level of Satb1 was highest before Treg cells develop, and
dropped after Treg cell development. Further study showed that Satb1
bound to the super enhancers responsible for Treg cell development, but
again, only in progenitors that differentiated into Treg cells and not
Treg cells themselves. Therefore, Satb1 may regulate the epigenetic
changes that precede the creation of Treg cells.
"Satb1 appears to be necessary for the differentiation of Treg cells,
but not for the maintenance of Treg cells," said Dr. Yohko Kitagawa,
who first-authored the study.
Indeed, in mice lacking Satb1, the development of Treg cells was
impaired and the mice showed symptoms of autoimmune disease.
Furthermore, the progenitors cells of these mice showed inferior super
enhancer activity, which resulted in less expression of the genes
necessary for Treg cell development.
Based on these findings, Sakaguchi theorizes that defective
Satb1-dependent super-enhancer establishment could be a cause of
autoimmune diseases and allergy. "Autoimmune diseases are due to
hyperactive immune systems. One cause is not having enough Treg cells.
Understanding how this occurs is an important step towards treating
autoimmune diseases," he said.