The price for a vigilant immune system that can pounce on tumor cells or pathogens is occasional friendly fire—an autoimmune attack. Scientists have now identified a new type of human T cell that quells assaults on healthy tissues, a finding that could suggest treatments for conditions as diverse as lupus and cancer. “It’s a major step forward in understanding how the immune response and autoimmunity are regulated,” says immunologist Harvey Cantor of the Dana-Farber Cancer Institute who wasn’t involved in the work.
Immunologists already know mice and people deploy one type of regulatory T cell—a subset called Tregs that sports the protein CD4 T—that suppresses autoimmune attacks. The newer enforcers belong to a category of T cells distinguished by a different surface protein, CD8. CD8 T cells are best known for killing infected or cancerous cells, but in mice, some of them also suppress misdirected T cells. Although researchers have long suspected humans have similar cells, nobody had confirmed their existence.
One obstacle was that humans don’t make the distinctive receptors that mark the subset of CD8 cells in mice. However, some human CD8 T cells flaunt comparable receptors, the KIR proteins. To determine whether these human cells are immune inhibitors, Jing Li, a postdoc in the lab of immunologist Mark Davis at Stanford University’s School of Medicine, and colleagues first measured their abundance in patients with autoimmune diseases such as multiple sclerosis, lupus, and celiac disease. The cells were more common in blood from patients than from healthy people, the team reports online today in Science. Tissue samples revealed they congregated in parts of the body damaged by the autoimmune attack, such as the joints in people with rheumatoid arthritis and the small intestine in people with celiac disease.
The researchers detected similar surges of the KIR-producing T cells in people fighting infections, especially the pandemic coronavirus. In 56 COVID-19 patients, “We saw the KIR-positive cells going through the roof,” Davis says. And the sicker COVID-19 patients were, the more of the cells they harbored. The cells’ numbers also shot up in patients with influenza, the team found.
To investigate the cells’ role in autoimmunity, the scientists homed in on celiac disease, an inflammation of the small intestine triggered by the gluten proteins in bread and other grain-based foods. In patients with the painful condition, certain immune cells called helper T cells recognize gluten proteins such as gliadin and then spill molecules that promote inflammation. But in cell culture studies, Li and colleagues found, human CD8 T cells carrying KIR proteins killed the gliadin-detecting helper T cells. “That really opened up a window for us to understand the biology of these [KIR+] cells,” Li says.
To find out how much protection the cells provide against autoimmunity, Li and her colleagues analyzed genetically altered mice that have 50% to 75% fewer of the suppressive CD8 cells than normal. After exposure to certain viruses that can trigger autoimmune disease, the rodents developed signs of damage such as kidney inflammation. In contrast, control mice with a full complement of suppressive CD8 T cells didn’t show evidence of autoimmune diseases after infections.
Cantor and other scientists are convinced the team has fingered the long-sought human counterparts to the rodent immune regulators. “The paper provides really solid data that these cells exist in humans,” says immunologist Nu Zhang of the University of Texas Health Science Center, San Antonio. They may have remained obscure because they “are rare and are easily missed,” accounting for only about 5% of CD8-positive T cells, Davis says.
Immunologist Stephen Jameson of the University of Minnesota Medical School says approaches that increase the cells’ abundance might help soothe difficult-to-treat autoimmune illnesses such as celiac disease. It’s also possible, he adds, that the cells are “sitting in tumors” and shielding them from immune attacks, in which case reducing their numbers could unleash a person’s immune system to fight cancer. Researchers have attempted to harness the traditional, CD4-carrying Tregs for therapies, but no treatments have been approved, Cantor notes. “The hope is that with this new set of regulatory cells, we can use them more efficiently.”
A key question is why the immune system needs another type of suppressive T cell when it already has Tregs. But Tregs are generalists that inhibit a variety of immune cells without killing them. Davis posits that the KIR-positive CD8 cells target particular T cells that switch on during an assault by a pathogen. Although these freshly activated T cells help clear the invaders, they can also attack healthy tissues. The KIR subclass serves as a “SWAT team” to kill off these potentially ruinous T cells once an infection is quelled, Davis proposes.
The explosion of KIR-positive CD8 T cells the researchers detected in patients with autoimmune diseases or COVID-19 may reflect an attempt to rein in destructive immune reactions—the immune overreaction to the novel coronavirus is what kills many COVID-19 patients in the end. How the suppressive CD8 cells distinguish T cells with self-destructive tendencies is one of the mysteries scientists still need to answer.