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Series GSE138891 Query DataSets for GSE138891
Status Public on Feb 08, 2021
Title Cytotoxic CNS-associated T cells drive axon degeneration in aging and myelin disease
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 1. Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon–myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration, but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages—important representatives of the innate immune system—are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging. Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses. Here we examine the role of cytotoxic CD8+ T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases but understudied in the aging CNS. We show that accumulation of CD8+ T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8+ T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify aging-related changes. Mechanistically, we provide evidence that CD8+ T cells drive axon degeneration in a T-cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8+ CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function. 2. Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct mutations in the PLP1 gene result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in these myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates the recruitment of T cells and neural damage, while later targeting of CNS-associated T cell populations is inefficient and has no effect on neurodegeneration. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant oligodendrocyte myelin. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.
Overall design To characterize CD8+ CNS-associated T cells we comprehensively analyzed their transcriptomic profiles using single-cell RNA sequencing of CD45highCD8+ T lymphocytes freshly sorted from 12- and 24-month-old brains, as well as from 12-month-old brains from mice with PLP mutations. A total of 5,017, 5,504, and 6,467 cells were captured and a median gene number per cell of 1,325, 1,279, and 1,283 could be retrieved for adult and aged cells and cells from myelin mutants, respectively.
Web link
Contributor(s) Groh J, Knöpper K, Arampatzi P, Yuan X, Lößlein L, Saliba A, Kastenmüller W, Martini R, Abdelwahab T, Stadler D
Citation(s) 37182098, 37117598
Submission date Oct 15, 2019
Last update date Jun 09, 2023
Contact name Antoine-Emmanuel Saliba
Phone +49-931-31-81341
Organization name Helmholtz Institute for RNA-based Infection Research
Street address Josef-Schneider-Straße 2 / D15
City Würzburg
ZIP/Postal code 97080
Country Germany
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (3)
GSM4121359 H7
GSM4121360 H8
GSM6267636 H9
BioProject PRJNA577691
SRA SRP225757

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SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE138891_RAW.tar 477.1 Mb (http)(custom) TAR (of H5, TAR)
GSE138891_README.txt 158 b (ftp)(http) TXT
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Raw data are available in SRA
Processed data provided as supplementary file

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