‘Military police’ cells arise to arrest infection-induced autoimmunity, study finds

A new study led by Stanford Medicine investigators has discovered that a set of immune cells is dedicated to dialing down the aggression of infection-fighting but quarrelsome fellow immune cells.

This “military police” squad, the study indicates, prevents overzealous confreres from picking fights with our healthy tissues and instigating autoimmunity.

These immune cells are known as KIR+CD8 cells — or, informally, suppressor-CD8 cells — and they may point to novel therapies for autoimmune diseases.

“Our translational goal is to develop drugs or procedures that make these suppressor-CD8 cells more active or prolific,” said Mark Davis, PhD, the Burt and Marion Avery Family Professor and a Howard Hughes Medical Institute investigator. “It also throws light on an important aspect of autoimmunity that we had no clear understanding of before.”

Because these cells appear to be important in many, if not most, autoimmune diseases, the finding could have a profound impact, he said.

A paper describing the study was published online March 8 in Science. Davis, a professor of microbiology and immunology and the director of the Stanford Medicine Institute for Immunity, Transplantation and Infection, is the senior author. The lead author is Jing Li, PhD, a postdoctoral scholar in Davis’ group.

Although more than 80 autoimmune diseases have been identified, “immunologists haven’t been able to reach a full understanding of how autoimmunity arises,” Davis said.

There’s evidence that infections play a role in initiating autoimmunity. A recent Stanford study showed that infection by the Epstein-Barr virus contributes to multiple sclerosis, an autoimmune disease in which the body’s immune cells attack the fatty sheaths that coat nerve cells in the brain.

But that insight takes immunologists only partway toward a complete understanding, Davis said. “Almost everybody gets infected by Epstein-Barr eventually,” he noted, “while fewer than in 1,000 go on to contract multiple sclerosis.”

So, there must be more to autoimmunity than mere infection. Suppressor-CD8 cells could be the long-sought piece of the puzzle, Davis said.

The mutiny called autoimmunity

Immune cells called T cells constantly patrol our tissues, read the surfaces of cells residing in those tissues and react strongly to telltale signs that things aren’t right within a cell. For example, they can tell if it’s been infected.

One prominent group of T cells is known as CD4 cells. When they find infected cells, CD4 cells react mainly by proliferating and squirting out signaling substances that encourage antibody production and recruit other types of immune cells to fight the pathogen.

Other T cells, called CD8 cells, recognize infected cells the same way CD4 cells do, but their reaction is different: They directly attack and kill the infected cells.

Any given T cell recognizes just one or a handful of molecular shapes. Collectively, though, T cells can recognize trillions. The random process by which T cells’ awesome shape-recognition diversity is generated results in the creation of some T cells capable of reacting to our own healthy cells as if they were the enemy.

It was long thought that such potentially dangerous cells are destroyed in the thymus, an organ whose job involves training newborn T cells and culling those that might turn on the body that produced them.

But in a 2015 paper published in Immunity, Davis and his colleagues demonstrated that, rather than outright snuffing out traitorous T cells as soon as they pop up, the immune system keeps many of them around — presumably because those cells, for all of their menacing capacity to attack healthy tissue, just might be able to recognize and react to cells infected by one or another type of pathogen.

“You get infected all the time,” Davis said. “Until about 100 years ago, it was commonplace for half of all kids to die from infectious diseases before reaching adulthood.” In contrast, autoimmunity affects fewer than 1% of children and young adults, he said.

You need an all-hands-on-deck response even if it means some of the recruits are thugs.

When they’re not needed, self-recognizing T cells have to be defanged in some way to prevent them from causing mischief. One way this may happen is that self-reactive T cells are simply tagged as potential troublemakers and then allowed to roam freely. This would do no harm because, as earlier research has shown and the new study confirms, the cells remain quiescent, causing no trouble, until a viral infection — or possibly the inflammation brought about by immune cells responding to it — brings out their sadistic side. It’s only then that suppressor-CD8 cells come out of the woodwork to destroy the tagged cells.

In a 2019 Nature paper, Davis and his associates showed in mice that a subset of T cells equivalent to human suppressor-CD8 T cells was crucial to preventing an experimentally induced autoimmune disease mimicking human multiple sclerosis. Stimulating those cells caused them to kill self-reactive CD4 cells that were inducing autoimmunity in the mice.

In the new study, the researchers obtained blood samples from patients with multiple sclerosis, celiac disease or lupus — three autoimmune disorders.

“Although suppressor CD8s are normally less than 2% of total CD8 cells in healthy patients’ blood,” Davis said, “we found that they were sky-high in some lupus patients — constituting upward of 25% of all CD8 cells — and abnormally high in many active celiac disease and in multiple sclerosis patients.”

In addition, suppressor-CD8 cells proliferated in the blood of patients with COVID-19 — especially in severe cases — and influenza. The researchers also found that suppressor-CD8 cells were prevalent in synovia, a liquid that lubricates bone joints, of patients with rheumatoid arthritis, an autoimmune disease, but not in the synovia of patients with osteoarthritis. Although it’s an inflammatory condition, osteoarthritis is not considered an autoimmune disease.

The correlation between infection or autoimmunity and the proliferation of suppressor-CD8 cells, by itself, could mean that the immune cells are inducing or exacerbating, rather than mobilizing to damp down, autoimmunity. But further experiments made it clear that “suppressor” accurately describes their role.

Autoimmunity tied to infection

Suppressor-CD8s aren’t looking for pathogen-infected cells, the new study shows. They specifically chase down and kill self-reactive T cells that are recruited to fight off an infection but that, left unchecked, might go on a rampage.

Celiac disease occurs when self-reactive CD4 cells attack intestinal tissues after those cells have been triggered by the presence of a metabolite of gluten, a substance found in wheat and rye. Suppressor-CD8 cells incubated with the metabolite in a lab dish selectively killed self-reactive CD4 cells that are triggered by the metabolite. But the suppressor CD8 cells left other CD4 cells unscathed.

In another experiment, ridding mice of the equivalent of human suppressor-CD8 cells exacerbated autoimmunity that developed after viral infections.

“Every time you get infected, we think your immune system relaxes its normal controls and unleashes all of its pathogen-recognizing cells,” Davis said. “In situations like this, you need an all-hands-on-deck response even if it means some of the recruits are thugs.”

Stanford’s Office of Technology Licensing has applied for patents on intellectual property associated with the study’s methods and findings. Davis, Li and Naresha Saligrama, PhD, a co-author of the study and former postdoctoral scholar at Stanford, are co-inventors on the patent applications. Davis is also involved in a start-up, Mozart Therapeutics Inc., focused on the clinical application of these discoveries.

Davis is a member of Stanford Bio-X, the Stanford Cardiovascular Institute, the Stanford Maternal and Child Health Research Institute, the Stanford Cancer Institute and the Wu Tsai Neurosciences Institute at Stanford.

Other Stanford co-authors of the study are former postdoctoral scholar Shin-Heng Chiou, PhD; Stanford ITI genomics manager Xuhuai Ji, MD, PhD; basic life science researchers Jing Guo, PhD, and Vamsee Mallajosyula, PhD; graduate students Michael Sikora and Joy Pai; postdoctoral scholars Vincent van Unen, PhD, Liang Chen, MD, PhD, Jiefu Li, PhD, and Nathan Bracey, PhD; life science research professional Julie Wilhelmy; former life science research professional Alana McSween; former graduate student Brad Palanski, PhD; Sean N. Parker Center for Allergy and Asthma research associate Gopal Krishna Dhondalay, PhD; former graduate students Maxim Zaslavasky, PhD, and Kartik Bhamidipati, PhD; Lucas Kipp, MD, clinical assistant professor of neurology and neurological sciences; Jeffrey Dunn, MD, clinical professor of neurology and neurological sciences; Ansuman Satpathy, MD, PhD, assistant professor of pathology; William Robinson, MD, PhD, professor of immunology and rheumatology; Lars Steinmetz, PhD, professor of genetics; Chaitan Khosla, PhD, professor of chemical engineering and of chemistry and director of Stanford’s Innovative Medicines Accelerator; PJ Utz, MD, professor of immunology and rheumatology; Yueh-Hsiu Chien, PhD, professor of microbiology and immunology; Nielsen Fernandez-Becker, MD, clinical associate professor of gastroenterology and hepatology; and Kari Nadeau, MD, PhD, professor of pulmonary and critical care medicine and director of the Sean N. Parker Center for Allergy and Asthma Research.

Researchers at the University of Washington; the University of Oslo; UC San Francisco; and the European Molecular Biology Laboratory in Heidelberg, Germany, contributed to the study.

The work was funded by the National Institutes of Health (grants U01AI140498 and U19AI057229), the Howard Hughes Medical Institute, the Stanford Diabetes Research Center, the National Center for Research Resources, the National Science Foundation, the Wilke Family Foundation, Merck, the Biomedical Advanced Research and Development Authority, the National Multiple Sclerosis Society, the Sean N. Parker Center for Allergy and Asthma Research and the Sunshine Foundation.