Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed oligodendrocytes in PLP1 mutant mice

• DOI: 10.1016/j.isci.2023.106698
• Publication Date: 2023-04-19T15:45:54Z
• Authors: Tassnim Abdelwahab; David Stadler; Konrad Knöpper; Panagiota Arampatzi; Antoine-Emmanuel ...; Wolfgang Kastenmü...; Rudolf Martini; Janos Groh
• Keywords: Components of the immune system; 0303 health sciences; 03 medical and health sciences; Model organism; Science; Q; Molecular neuroscience; Article

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 PLP1 mutations result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates T cell recruitment and neural damage, while later targeting of CNS-associated T cell populations is inefficient. 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.