Scientists at Stanford University School of Medicine have identified a type of immune system cell that may point to the development of new therapeutic strategies against autoimmune disorders such as multiple sclerosis (MS) and celiac disease. Findings from the team’s studies in a mouse model of MS, along with preliminary analyses of cells from patients with MS, indicated that a subset of CD8+ T cells—a type of immune system cell that typically acts to kill infected or cancer cells—may act to suppress the pathogenic CD4+ and γδ+ T cells that promote autoimmune disease. Their results suggest that inflammatory and suppressive immune cells work to balance each other, and that selectively activating the suppressive CD8+ T cells during autoimmune diseases may restore the balance.

“We absolutely think that something like this is happening in human autoimmune diseases,” commented research lead Mark Davis, PhD, professor of microbiology and immunology, who holds the Burt and Marion Avery Family professorship, and is also a Howard Hughes Medical Institute investigator. “If we could mobilize those cells to function more effectively in patients with autoimmunity, then we’d have a novel treatment for diseases like multiple sclerosis.” Davis and colleagues report on their findings in a paper in Nature, which is titled, “Opposing T cell responses in experimental autoimmune encephalomyelitis.”

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Autoimmune diseases affect an estimated 23.5 million people in the United States, and in most cases, such as MS, it is not known what the molecular triggers are. There are some insights, however. Celiac disease is an autoimmune condition in which gluten consumption triggers the immune system to attack the small intestine. Prior research had shown that for affected individuals, exposure to gluten triggers the production of gluten-specific CD4+ T cells, and also gut-homing CD8+ and γδ+ T cells.

Experimental autoencephalomyelitis (EAE) is a mouse model for MS that ultimately results in paralysis. The disorder is triggered by injecting the mice with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide. Davis and colleagues wanted to know whether the same coordinated T-cell response that had been seen in the celiac disease study might also occur in EAE.

Tracking levels of different classes of immune cells in mice injected with MOG confirmed that the coordinated T-cell response evidenced in celiac disease did also occur in EAE, both in the blood and in the central nervous system. The scientists found that in EAE the numbers of T cells rose and fell in waves, and DNA sequencing showed that the waves were each made of groups of identical cells.

“When T cells encounter a pathogen, or antigen, single cells that recognize some part of the pathogen divide and produce many copies of themselves,” explained research associate Naresha Saligrama, PhD, the study’s lead author. “This suggested that a specific population of cells were responding.”

The researchers then needed to find out what these T cells were responding to. The most obvious candidate was MOG, so Saligrama exposed the expanded cells to 350 MOG-derived peptides. He found that while the peptides did trigger some types of T cell to proliferate, there was a subset of the CD8+ T cells that didn’t respond to any of the MOG peptides. “Although the expanded CD4+ T cells are largely specific for the myelin oligodendrocyte glycoprotein (MOG) immunogenic peptide 35–55 (MOG35–55), clonally expanded CD8+ T cells were nonresponsive to myelin peptides or proteins,” the authors wrote.

To discover what these CD8+ cells were reacting to, the team harnessed yeast display technology to generate a 5 billion peptide array, against which they screened six CD8+ T cell receptors (TCRs). “We are crowdsourcing the T cells,” Davis explained. “We’re asking the T cells, as the disease is progressing, what they are interested in. We’re not trying to guess or hypothesize what they are recognizing.”

The screen found two peptides (surrogate peptides, or SPs) that were recognized by two of the CD8+ TCRs. The next step was to see what happened when they injected these peptides into the mice, either before, alongside, or after MOG. The researchers expected that injecting the peptides into EAE-induced mice would activate the CD8+ cells that recognized them, and worsen disease. Surprisingly, however, what they found was exactly the opposite. Injections of the two peptides activated the CD8+ T cells, but this reduced or even prevented disease in the mice. “Whereas MOG immunization induced severe disease in 100% of the mice, the addition of SP with MOG resulted in much less severe or no disease, with only a 30% incidence of very mild disease, with most mice exhibiting no symptoms at all.”

Tests indicated that these expanded CD8+ T cells were in fact suppressing the disease-promoting CD4+ T cells. “Further analyses show that these T cells represent a unique subset of regulatory CD8+ T cells that suppress MOG35–55-specific CD4+ T cell proliferation, which suggests that the induction of autoreactive CD4+ T cells in EAE triggers a counteracting wave of regulatory CD8+ T cells,” the investigators commented.

Experiments in lab dishes indicated that the surrogate peptide-activated CD8+ T cells were killing disease-promoting cells by punching holes in their membranes. The CD8+ T cells were also expressed cell surface proteins associated with immunosuppression.

The concept of the existence of immunosuppressive CD8+ T cells isn’t new. The idea was first mooted back in the 1970s, but didn’t gain ground due to lack of evidence. “Suppressor CD8 T cells did for immunology what the Titanic did for the cruise industry,” Davis noted.

Having established the existence of the regulatory CD8+ T cells in the EAE mouse model, the next stage was to see whether equivalent cells were also produced in humans with MS. The researchers’ tests found that, similar to their observations in EAE mice, people with newly diagnosed MS also tended to have large expanded populations of single cell-derived CD8+ T cells, which hinted that that CD8+ T cells in MS patients were also being activated against a specific target. “These results suggest that the induction of autoreactive CD4+ T cells triggers an opposing mobilization of regulatory CD8+ T cells,” the scientists noted. “We show here that the simultaneous mobilization of oligoclonal T cells, seen previously in patients with celiac disease, has a parallel not only in EAE, but also to some extent in newly diagnosed patients with MS.”

Davis and team are now working to find out what these human CD8+ T cells are recognizing, and whether some of them are suppressive. They also hope to discover whether these CD8+ T cells are involved in other autoimmune diseases. “Most importantly, given the similarities described above in the dynamics of T cell responses in celiac disease, EAE, and MS, it seems likely that pathogenic CD4+ and γδ+ T cell responses opposed by regulatory CD8+ T cells responses may be a common phenomenon across autoimmune diseases,” they concluded.

The authors say their study highlights the importance of the investigative approach taken. “… our study shows the value of studying T cell specificity and activity from ‘the ground up’; that is, identifying the T cells that are most active in a given response by single-cell paired TCR sequencing … This is in contrast to traditional methods that typically involve knowing (or guessing) what the relevant antigens are.”

“Crowdsourcing T cells is a fundamentally different way to look at disease,” Davis said. “This project shows not only the power of this approach but the power to discover new mechanisms.”

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