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Luring T cells into a gray area

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Science Immunology  05 Apr 2019:
Vol. 4, Issue 34, eaax3917
DOI: 10.1126/sciimmunol.aax3917

Abstract

T cells that target β-synuclein induce damage to the gray matter of the brain in multiple sclerosis and contribute to neurodegeneration.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that typically results in intermittent neurological manifestations followed by the progressive, irreversible accumulation of clinical and cognitive deficits. Neurodegeneration is also observed in a subset of patients. MS was long considered a disease of the white matter based on the presence of immune cell–mediated demyelinating lesions targeting neuronal axons in this area of the brain in the early remitting-relapsing stage of the disease. However, white matter lesions alone cannot explain the later-stage cognitive symptoms that reflect gray matter damage. In addition, little is known about the later progressive stages of the disease due to the lack of animal models.

Lodygin and colleagues used rat models and blood samples from MS patients to study T cells specific for β-synuclein. This protein is abundantly present in the plaques seen in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease, suggesting that it might be a potential target in autoimmune conditions. The authors established T cell lines specific to β-synuclein (Tβ-syn) or myelin basic protein (TMBP); they also generated a T cell receptor (TCR)-transgenic rat model from which β-synuclein–specific T cells were intravenously transferred into healthy rats. Fluorescence microscopy showed TMBP cells infiltrated the white matter of the brain and spinal cord, as expected, in recipient rats, while Tβ-syn cells mostly invaded gray matter. Multiphoton microscopy and RNA-sequencing showed that the two cell types undertook similar migratory paths and that T cell entry into white or gray matter was linked to the location of the target antigen and not to differences in chemokines or cues for adhesion. The authors also discovered that similar types of T cells were abundant in the blood of patients with MS. While β-synuclein–specific T cells were mainly increased in patients with chronic progressive MS, myelin-reactive T cells were predominant in patients with relapsing-remitting MS. This study has revealed that the gray matter is an important target tissue in immune-mediated neurodegeneration, and it has opened up new research opportunities to model immune activities within this area of the brain.

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