Twin study illuminates how turncoat T cells launch nervous system assaults in multiple sclerosis

Few autoimmune disorders are more challenging for patients than multiple sclerosis, a progressive condition that can affect vision, impair the ability to walk, cause extreme bouts of neuropathic pain, and tends to strike women at three times the rate of men.

New findings from a large team of researchers in Germany involving twins may provide the clearest insight to date illuminating the role of cytotoxic T cells—CD8⁺ T cells—in the progression of multiple sclerosis, also simply referred to as MS.

The disorder is a chronic autoimmune disease of the central nervous system characterized by the immune system’s assault on the protective myelin sheaths of nerves. Irrevocable demyelination—loss of the fatty insulation surrounding nerves—interferes with the conveyance of nerve impulses between brain and body. Medicines can help control the disease, slowing progression and easing pain, but there is no cure.

Exactly how—and why—turncoat T cells unleash their attacks in multiple sclerosis has been the subject of intense research for decades. Indeed, medical scientists have sought a deeper understanding of the cascade of deleterious events that underlie the inflammation and episodes of waxing and waning—flare-ups and remissions—that indelibly mark the disease.

Led by researchers at the Institute of Clinical Neuroimmunology at University Hospital, a division of Ludwig Maximilian University of Munich, scientists sought to demystify the role of CD8⁺ T cells, the dominant immune system constituents in the inflammatory autoimmune disorder.

“CD8⁺ T cells are abundant within MS lesions,” writes the study’s lead author, Vladyslav Kavaka in the journal Science Immunology. Kavaka and colleagues, who hailed from multiple divisions throughout University Hospital in Munich, also collaborated with team members at the University of Heidelberg.

“We compared CD8⁺ T cell clones from the blood and cerebrospinal fluid of monozygotic twin pairs in which the co-twin had either no or subclinical neuroinflammation,” Kavaka added.

While T cells are highly proliferative in MS lesions, researchers had not fully understood how the cells contributed to the condition. The German team also knew that MS is affected by patients’ genetics and the environment. But studying people of varied genetic backgrounds didn’t boost the understanding of how heritable factors influenced the course of the disease over time.

The same was true of the environment. When studying volunteers of different environmental backgrounds, it was difficult to tell which environmental factors most affected the disease.

Choosing twins allowed a better way to trace the activities of CD8⁺ T cells because the patients were genetically identical and lived in similar environments. In the study, scientists required that one sibling already have a diagnosis of MS. The other had to have at least a 25% chance of developing the condition. Some in the “co-twin” group showed no signs of MS at all, while others had subclinical neuroinflammation, the earliest detectable disease stage.

Using single cell transcriptomics and T cell receptor sequencing, researchers studied CD8⁺ T cells in 12 pairs of monozygotic twins; 12 people with MS; six co-twins affected by subclinical neuroinflammation, and six clinically healthy co-twins.

What German scientists discovered has produced a turning point in the understanding of CD8⁺ T cells and their complex role in multiple sclerosis. The team found that CD8⁺ T cells are potently involved in the disorder’s hallmark inflammation.

Moreover, in people with MS and subclinical neuroinflammation, CD8⁺ T cells in the peripheral blood and cerebrospinal fluid expressed genes associated with increased activation, antigen presentation, cytotoxic signaling, and energy production.

MS-associated CD8⁺ T cells also possessed a heightened potential to travel to the central nervous system and recruit other immune cells to sites of neuroinflammation. Having new insight into the activities of CD8⁺ T cells can inform novel ideas on future therapeutic targets, Kavaka and colleagues say.

Awareness of cytotoxic T cells’ link to MS didn’t emerge in recent months or with the German scientists’ T cell research. Immunologists worldwide have long recognized that CD8⁺ T cells are associated with the condition. Scientists have known for years that the CD8⁺ T cell population is intimately linked with disease progression. But even though these facts were evident, the disease-specific activities of these critical immune system cells remained elusive.

Kavaka and colleagues say their research opens a new window of understanding about the role of CD8⁺ T cells—the dominant turncoats—in the autoimmune assault on nerves in multiple sclerosis.

“We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8⁺ T cell phenotype, which was also evident in co-twins with subclinical neuroinflammation and in an independent validation cohort of people with MS,” Kavaka and colleagues concluded.

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