NOV 30, 2022 5:22 PM PST

Rogue, Cancer-Linked Immune Cells Found to Drive Autoimmune Disorders

WRITTEN BY: Carmen Leitch

Leukemia patients are more likely to get autoimmune disorders like aplastic anemia or rheumatoid arthritis than unaffected people. Research has suggested that immune cells known as killer T cells are involved this process. There are small changes or variants in the sequences of genes that have been associated with a wide variety of diseases, including leukemia. Now, scientists have discovered gene variants that can trigger activity from so-called rogue immune cells that promote autoimmune disease in leukemia patients. These genetic variants affect the protein that is produced and influence the growth of killer T cells, which can also turn them rogue. The findings have been reported in the journal Immunity.

A killer T cell (centre) hunting a target cell. Credit: NIH Image Gallery

“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,” noted first study author Dr. Etienne Masle-Farquhar, a postdoctoral researcher at the Garvan Institute of Medical Research.

The study has also identified biochemical pathways that could be useful treatment targets in these disorders as well, noted Masle-Farquhar.

The immune system has to respond immediately to danger, such as that posed by cancer cells or pathogenic invaders, and it also has to be carefully controlled. Autoimmune diseases can arise when the immune system erroneously attacks the tissues of the body, or when the inflammation caused by an immune response is not turned off when it should be.

Rogue T cells are often found in people with different autoimmune disorders, but inflammation can also cause the growth or mutation of immune cells. In this study, the researchers wanted to know whether the rogue T cells were causing autoimmune disease, or if they were just linked to those disorders, added Masle-Farquhar.

Mutations that arise during a person's lifetime, instead of inborn mutations, are called somatic mutations. Somatic mutations in a gene called STAT3 have been linked to cases in which leukemia arises in patients with autoimmune disease. Using the CRISPR/Cas9 gene editing technique, the researchers modeled the STAT3 gain-of-function mutations in mice. The STAT3 gene encodes for proteins that play a crucial role in the control of B and T cells of the immune system. The work showed that these mutations can cause the unchecked growth of rogue T cells, which generates huge cells that can bypass the checks on the immune response to attack the body's own tissues. Specifically, the STAT3 mutation was found to drive the buildup of effector CD8+ T cells that express high levels of NKG2D.

The study suggested that an autoimmune disorder can arise even when only one to two percent of an individual's T cells goes rogue in this way.

This research has solved a conundrum about whether cancer cells were acquiring STAT3 mutations and autoimmunity was the result, or if STAT3 mutations were actually promoting disease, said  Professor Chris Goodnow of Garvan.

This study can also help scientists find better medications to treat the effects of these mutations. Scientists and clinicians may one day screen patients for T cells that carry STAT3 mutations to locate the harmful cells, added Goodnow.

Two biochemical pathways are involved in this process, one of which is linked to stress.

“Part of what’s driving these rogue cells to expand as killer T cells is the stress-sensing pathways. There is a lot of correlation between stress, damage, and aging. Now we have tangible evidence of how that’s connected to autoimmunity,” added Goodnow.

These rogue T cells may also be related to other autoimmune diseases, but more work will be needed to find the answer to that question.

Sources: Garvan Institute of Medical Research, Immunity

About the Author
Bachelor's (BA/BS/Other)
Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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