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T Cell Gene Expression In Multiple Sclerosis CSF Reflects Elevated Activation, Cytotoxicity

NEW YORK – T cells isolated from the cerebrospinal fluid of people with multiple sclerosis express higher levels of genes linked to T cell activation and cytotoxicity than those from the CSF of healthy people, according to a new single-cell RNA sequencing study.

Despite the blood-brain and blood-cerebrospinal fluid barriers, T cells surveil the central nervous system via the CSF for pathogens. At the same time, however, they may contribute to neuroinflammation in conditions like MS.

Researchers led by Yale School of Medicine's David Hafler used both single-cell RNA-sequencing and T cell receptor sequencing to study T cells from the blood and CSF of healthy individuals and then compare them with T cells from individuals with MS. As they reported in Science Immunology on Friday, the researchers uncovered various clusters of T cells and noted differences in gene expression between the T cells of people with MS and healthy individuals.

"Overall, our work has generated a single-cell RNA and TCR dataset that has allowed the integration of transcriptional and clonal information to further understand T cell surveillance of the CNS in healthy individuals and patients with MS," Hafler and his colleagues wrote.

He and his colleagues first profiled the transcriptomes of single cells isolated from the peripheral blood and CSF of six healthy donors, a total of 50,483 cells. As expected, the CSF samples contained primarily T cells, though monocytes and dendritic cells were also present. Using a tool for visualizing high dimensional data, the researchers noted a phenotypic continuum of T cells between blood and CSF samples.

Still, they noted two main cell clusters present in the blood, one composed of naive CD4 cells and one of naive CD8 cells. CSF, meanwhile, harbored three clusters of memory CD4 T cells and one memory CD8 cluster, consistent with previous work indicating naive T cells are rare in CSF.

The researchers also generated a score reflecting how blood-like or CSF-like a cell is to further characterize that phenotypic continuum. Cells that were more CSF-like had increased expression of genes linked to T cell exhaustion and TH1 function pathways and decreased expression of TH cell differentiation and interleukin-7 signaling pathways.

They additionally noted that expanded CSF T cells in the CSF of healthy people represented a more extreme T cell state.

The researchers also examined immune cells present in the CSF of five individuals newly diagnosed with MS. People with MS, they noted, had an increased number of B cells present in their CSF, but still had a similar distribution of naive and memory T cell clusters in their blood and CSF compared to healthy controls. At the gene expression level, however, they noted a number of differences. For instance, genes involved in TCR engagement and T cell activation were more highly expressed among MS patients compared to controls. 

These differences in gene expression were particularly noticeable in clonally expanded T cells among MS patients. Many of these genes were linked to T cell activation, cytotoxicity, and an effector phenotype. 

The analysis, the researchers noted, sheds light on the immune environment of the CSF, both in healthy individuals and in people with neuroinflammation.