A new study in mice by researchers at the Garvan Institute of Medical Research demonstrates that gene variants associated with leukemia can produce “rogue” immune cells that drive autoimmune diseases.
The findings are published in the journal Immunity in an article titled, “STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological dysregulation and accumulation of NKG2Dhi CD8+ T cells.”
“The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co-existing autoimmunity,” wrote the researchers. “To investigate whether these mutations are the cause or consequence of CD8+ T cell clonal expansions and autoimmunity, we analyzed patients and mice with germline STAT3 GOF mutations.”
Scientists had previously noted that leukemia patients were also likely to develop an autoimmune disease, such as rheumatoid arthritis or aplastic anemia. Further research into this link revealed that immune cells called killer T cells were key players.
“We showed that these rogue killer T cells are driving the autoimmunity. They’re probably one of the cell types most directly contributing to autoimmune disease,” said Etienne Masle-Farquhar, PhD, a postdoctoral researcher in the immunogenomics and genomic medicine labs at Garvan.
“Our research also narrows down a few pathways that might be helpful in targeting these cells for future treatments,” he said.
“We knew that people with various autoimmune diseases acquire these rogue killer T cells over time, but also that inflammation can cause immune cells to proliferate and develop mutations. We set out to discover whether the rogue T cells were causing these autoimmune conditions, or simply associated with them,” said Masle-Farquhar.
The researchers used new high-resolution screening methods to look at blood from children with rare inherited autoimmune diseases. They then used CRISPR/Cas9 in mouse models, to observe what happens when the protein STAT3 is genetically altered.
The team discovered that if STAT3 is altered, it can cause rogue killer T cells to grow unchecked, resulting in enlarged cells that bypass immune checkpoints to attack the body’s own cells.
“It’s never been clear what the connection between leukemia and autoimmune disease is— whether the altered STAT3 protein is driving disease, or whether leukemic cells are dividing and acquiring this mutation just as a by-product. It’s a real chicken-and-egg question, which Masle-Farquhar’s work has been able to solve,” said Chris Goodnow, PhD, head of the immunogenomics lab and chair of the Bill and Patricia Ritchie Foundation at Garvan.
“This gives some really good cracks in the coalface of where we might do better in terms of stopping these diseases, which are sometimes life threatening,” he said.
Future applications could include better targeting of medication, like already TGA-approved JAK inhibitors, based on the presence of these mutations. “We can now go and look for T cells with STAT3 variations. That’s a big step forward in defining who’s the bad guy,” said Goodnow.
Further study is needed to determine whether rogue killer T cells are involved in all autoimmune diseases, and what proportion of people with rheumatoid arthritis and other autoimmune conditions have rogue cells and STAT3 variations.