Transcriptomic and clonal characterization of T cells in the human central nervous system

ABSTRACT: Tissues develop unique homeostatic immune states through specific recruitment of immune cells that are further shaped by the tissue environment. Here, we use single-cell RNA and TCR sequencing of healthy cerebrospinal fluid (CSF) and single-nucleus RNA sequencing of brain parenchyma to profile the T cell state in the human central nervous system (CNS). We observe a continuum of T cell states, reflecting a blood-CSF “axis”, that we use to reveal that T cells in the CSF largely exhibit a tissue-resident phenotype with a balance of co-inhibitory and effector function gene expression, including PD-1+ T cells retaining the ability to produce IFNg. Leveraging paired single-cell TCR sequencing to identify clonal T cell groups, we find that T cell phenotypes mirror the tissue where they reside and that clonally-expanded T cells reflect the most CSF-distinct state. To identify how this T cell state is perturbed during neuroinflammation, we profiled newly-diagnosed, treatment-naive patients with multiple sclerosis (MS) and observed that clonally expanded T cells are the most phenotypically different between patients and healthy controls. We then identify putative pathways of communication between T cells in the brain parenchyma and glia and neurons that may be involved in shaping T cell function. Our elucidation of the CNS T cell state provides context for understanding neuroinflammation and neurodegeneration as well as providing a framework for understanding tissue-driven T cell adaptation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157277 | GEO | 2020/09/02

REPOSITORIES: GEO