Specific genes allow immune T-cells to infiltrate the brain, study finds

Researchers have identified nearly two dozen genes that help to control the movement of immune cells into the brain and spinal cord during multiple sclerosis (MS).

Findings may form the basis for the further development of MS treatments that aim to reduce disease activity by blocking the infiltration of inflammatory immune cells into the brain.

The study, “A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model,” was published in Nature Neuroscience.

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T-cell movement into the brain is a known, key process in MS

MS is caused by inflammation that damages the brain and spinal cord, collectively called the central nervous system or CNS. Inflammation in the disease is driven by immune cells such as T-cells, which move from the blood into the CNS to trigger inflammation.

The migration of T-cells into the brain and spinal cord is a key part of the biological process that drives MS, and could be a useful strategy in new treatment development. However, the exact mechanisms that control the movement of T-cells into the CNS aren’t fully understood.

“We lack a comprehensive understanding of the essential molecular cues and signaling streams that enable or limit T cell entry to the CNS and may thus represent alternative targets for therapy,” the researchers, all in Germany, wrote.

A team at Ludwig-Maximilians-Universität München set out to identify genes that are needed for T-cells to get into the CNS in a rat model of the disease. For their study, the researchers used a gene editing technique called CRISPR to delete thousands of individual genes from T-cells, then evaluated whether the cells were more or less able to get into the CNS.

This screen revealed 18 genes that are essential for T-cells entering the CNS — when any of these genes were deleted, the number of T-cells in the rats’ central nervous system was significantly reduced.

Several of these genes, including ITGA4, FERMT3 and HSP90B1, code for proteins that T-cells use to stick to the walls of blood vessels, which helps the cell to stop moving and leaving the blood. Other genes like CXCR3 and GNAI2 are involved in sensing signaling molecules that are used to direct the movement of immune cells.

Several MS therapies work to restrict the migration of autoreactive T-cells

The genes GRK2 and S1PR1 both were needed for T-cells to squeeze through blood vessel cells and into the CNS. The researchers noted that the S1PR1 gene encodes a protein that is targeted by S1P receptor modulators, a class of medication that includes Gilenya (fingolimod), Mayzent (siponimod), Ponvory (ponesimod), and Zeposia (ozanimod), which are used to treat MS because they can prevent the movement of immune cells into the blood.

“Our investigation has confirmed for the autoreactive T cells we studied that key molecules of the mechanism are already the target of MS therapies and are being employed in clinical practice,” Martin Kerschensteiner, a study co-lead author and director of the Institute of Clinical Neuroimmunology at the Munich university, said in a press release.

Among the genes needed for T-cells to enter the CNS, there were some that also encode transcription factors such as TBX21. Transcription factors are proteins that help to control the activity of other genes in a cell to regulate the cell’s overall genetic activity.

In addition to the genes whose deletion prevented T-cells from getting into the CNS, the researchers also identified five genes that, when deleted, led to increased T-cell migration into the CNS — which implies that these genes normally help to “put the brakes” on T-cell migration.

The gene with the strongest effect was the transcription factor ETS1, and data suggested that T-cells lacking ETS1 also are more pro-inflammatory once inside the CNS.

While this study was mainly done in rats, the researchers conducted experiments using human T-cells to demonstrate that many of these genes play similar functions in people. Analyses of cells from four people with MS also showed these genes are expressed in patients’ T-cells.

“Taken together, our study thus helps to define the essential molecules and modules that govern … T cell trafficking to the CNS and demonstrates their regulated expression in individuals with MS,” the scientists concluded.

Study findings could form the basis for future work to explore strategies to treat MS by stopping the movement of T-cells into the CNS, the researchers said. They also noted that their CRISPR-based genetic screening strategy might be employed in future studies to investigate other processes that drive MS.