Viral Infection Promotes Factor in T-cells Leading to Brain Tissue Destruction

Infection with lymphocytic choriomeningitis virus triggers expression of a factor called TOX in immune cells strengthening their migration into the brain and promoting damaging effects, including inflammation and tissue destruction.

These findings represent a new piece of the puzzle about the mechanism underlying autoimmune diseases  like multiple sclerosis (MS).

The study “Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8⁺ T Cells,” was published in the jounal Immunity.

The bulk of currently available therapies for MS are capable only of managing disease symptoms, without targeting and resolving the disease’s underlying causes.

But the causes of MS, however, are still a mystery. Researchers know that both genetic and environmental factors participate in the disease onset, but why only certain people develop MS is far from clear.

Researchers at the University of Geneva (UNIGE) and Geneva University Hospitals (HUG), Switzerland, decided to investigate the link between infections and MS.

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“We decided to [analyze] the infectious factors by studying the auto-immune reactions provoked by different pathogens,” Doron Merkler, study lead author, said in a press release. Merkler is a professor in the Pathology and Immunology Department in UNIGE’s faculty of medicine and in the HUG Clinical Pathology Department,

“This was to try to pinpoint an element that might influence the development of multiple sclerosis where there has been an infection,” Merkler added.

The team injected two pathogens – a bacteria called Listeria monocytogenes and the lymphocytic choriomeningitis virus – in healthy mice and looked at the animal’s immune responses, analyzing specifically a pool of immune cells called CD8 T-cells.

“We saw a quantitatively identical immune reaction from the lymphocytes called CD8+ T,” said Nicolas Page, study’s first author and a researcher at UNIGE’s. “However, only the mouse infected with the viral pathogen developed an inflammatory brain disease reminiscent to multiple sclerosis.”

They then looked deeper into the genes of the CD8 T-cells and how each pathogen influenced their activation.

Researchers found that TOX, a DNA-binding factor, was only activated during the lymphocytic choriomeningitis virus infection. Moreover, TOX activation was essential for inflammation in the brain.

“We found that the inflammation environment influences the expression of TOX in T lymphocytes, and that it could play a role in triggering the illness,” said Page.

The team then transferred CD8 T-cells depleted of TOX into a mouse model of brain inflammation that  had been infected with the viral pathogen. Although the animals received the virus, researchers saw they failed to develop MS-like symptoms.

The researchers suggest that TOX alters the expression of receptors at the surface of CD8 T-cells that prevent these cells from migrating into the central nervous system, inducing damage.

When analyzing human MS lesions, researchers also found infiltrating T-cells expressing TOX.

“This is an encouraging result for understanding the causes of the disease but there is still lots of work to be done to ascertain what really causes multiple sclerosis in humans,” said Page.

The team plans to further investigate the activity of Tox and its involvement in auto-immune diseases.

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