Author:
Abdelwahab Tassnim,Stadler David,Knöpper Konrad,Arampatzi Panagiota,Saliba Antoine-Emmanuel,Kastenmüller Wolfgang,Martini Rudolf,Groh Janos
Abstract
SummaryMyelin 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 thePLP1gene 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 myelinating oligodendrocytes. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.
Publisher
Cold Spring Harbor Laboratory