January 30, 2020

T cells are immune cells that play an important role in fighting pathogens like viruses and bacteria, but some T cells can trigger damage in lupus if not properly controlled. VISTA, a protein on the surface of T cells, can keep the T cells from causing harm by keeping them dormant unless activated by proper targets, according to a study led by Dr. Randolph Noelle of the Dartmouth Geisel School of Medicine, who received the Dr. William E. Paul Distinguished Innovator Award in Lupus and Autoimmunity from the Lupus Research Alliance. Published in the prestigious journal Science, these new results reveal insights about how the immune system keeps itself in check and supports the idea that drugs that activate VISTA could help treat lupus patients.

T cells have proteins on their surface (receptors) that can bind or attach to pathogens—this activates the T cell and allows it to kill the bacteria or virus.  Scientists have known that there also are abnormal T cells that can be activated by harmless molecules in the body, but normally these T cells are kept in check so they don’t cause damage.

But what wasn’t known is how the immune system keeps these abnormal T cells in check. In 2011, Dr. Noelle and his colleagues discovered that a protein VISTA serves as a brake for T cells, keeping them in a ‘dormant’ state until needed to  attack.  Interestingly, they also found that mice prone to lupus develop symptoms faster if they lack VISTA. With his 2014 Distinguished Innovator Award, Dr. Noelle further explored VISTA’s role in lupus and developed antibodies that can activate VISTA so the T cells remain dormant.  Early data also showed that there was a lower level of VISTA in aging mice prone to lupus.

In a new study that builds on this work, Dr. Noelle and his team learned more about how VISTA works. They analyzed T cells from genetically modified mice that did not have the VISTA protein. They found that without any VISTA, more T cells were activated in the mice, which suggests that VISTA normally keeps the cells switched off. The researchers also found that the T cells in the mice were kept in this inactive state by certain genes that were turned on in the T cells.  When they compared these T cells in the mice that lacked VISTA with the T cells from humans with lupus and rheumatoid arthritis, they found  similar genes were turned on. This discovery provides more evidence that VISTA helps prevent the immune system from attacking patients’ tissues.

These findings add to the evidence that stimulating VISTA could reduce lupus symptoms caused by T cells. A company that Dr. Noelle co-founded, ImmuNext, is developing anti-VISTA antibodies that turn on VISTA and could be potential treatments for lupus.