Tumor Suppressor Protein Plays Key Role in Maintaining Immune Balance

In a research published online in the scientific journal “ Nature Immunology, it is revealed that scientists at the St. Jude Children's Research Hospital have discovered that a protein known to be suppressing tumor formation can also help in preventing autoimmune diseases and other problems by putting the brakes on the immune response.

The tumor suppressing protein PTEN is crucial for the proper functioning of regulatory T cells. This small population of white blood cells helps in maintaining the balance in immune system by suppressing specialized T cells called helper T cells that trigger distinct parts of the immune response. The helper T cells which were a part of this study included type 1 T helper (Th1) and follicular T helper (Tfh) cells.

In order to combat infections and to prevent misguided immune attacks that lead to autoimmune diseases and other problems, both regulatory T cells and helper T cells should play their roles. However, how the regulatory T cells control the diverse functions of various helper T cells was not known. The aim of this study was to fill in the gaps by understanding how the control process works, particularly PTEN’s role. This research also focussed on a new area to improve treatment of autoimmune diseases.

PTEN is one of the most frequently altered tumor suppressor genes in human cancers. Additionally, loss of the protein is also tied to autoimmune problems. According to this study, PTEN is required to maintain the stable population of regulatory T cells which in turn keeps the immune system in check. It is known that loss of PTEN in humans leads to the formation of tumors. Author Hongbo Chi, Ph.D., a member of the St. Jude Department of Immunology remarked that this study highlights another role and shows that PTEN is imperative for proper functioning of regulatory T cells and prevention of autoimmune diseases. He added that in mice, even the loss of one copy of the PTEN gene in regulatory T cells is enough to set the stage for autoimmune problems.

For this study, the researchers worked on specially bred mice and by deleting the PTEN gene in regulatory T cells they found that it was followed by a dramatic increase in the number of Tfh and related cells. Tfh cells typically help in production of antibodies, which combat infections. However, when they are produced inappropriately, antibodies trigger autoimmune disorders like lupus.  The mice used for this experiment developed kidney damage and immune changes associated with lupus. Even after the PTEN was restored to 50 percent of normal levels, it did not protect the mice from inflammatory disease.

On further research, it was found that Th1 cells influences the activity of Tfh cells. These cells produce a chemical messenger interferon gamma that triggers the immune response. on blocking the interferon gamma production in the specially bred mice, the researchers found that the number of Tfh cells fell and also there was a decrease in lupus-like immune abnormalities.

Sharad Shrestha, a graduate student in Chi’s laboratory and the study's first co-author remarked that by identifying the crucial role of PTEN in controlling Tfh cells and autoantibody production and by linking the role of PTEN to Tfh cells, they have opened doors for further investigation of Tfh related lymphomas.

Kai Yang, Ph.D., a staff scientist in Chi’s laboratory and also the study's co-first author said that the results of the study reveal a hierarchy of control that regulatory T cells use to simultaneously regulate Th1 and Tfh cells. They have found evidence that Th1 production of interferon gamma is a pre-requisite for the activity of Tfh cells.

This study also found insights into a cell signaling pathway that regulates many important functions, including T cell activity like the mTOR pathway, in which the protein complexes mTORC1 and mTORC2 play central roles. By deleting PTEN in regulatory T cells there was an increased activity of mTORC2 but not mTORC1. When scientists blocked mTORC2 activity in mice whose regulatory T cells lacked PTEN, immune system balance and activity returned to normal.

This PTEN-mTORC2 axis provides another avenue for scientists so that better treatments for autoimmune and other disorders can be developed.