A CD8<sup>+</sup> NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis.
Smilek, Dawn E
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McKinney, E., Cuthbertson, I., Harris, K. M., Smilek, D. E., Connor, C., Manferrari, G., Carr, E. J., et al. (2021). A CD8<sup>+</sup> NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis.. Nature communications, 12 (1), 635. https://doi.org/10.1038/s41467-020-20594-2
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with the majority of cases characterised by relapsing/remitting (RRMS) attacks of neurologic dysfunction followed by variable resolution. Improving clinical outcomes in RRMS requires both a better understanding of the immunological mechanisms driving recurrent demyelination and better means of predicting future disease course to facilitate early targeted therapy. Here, we apply hypothesis-generating network transcriptomics to CD8+ cells isolated from patients in RRMS, identifying a signature reflecting expansion of a subset of CD8+ natural killer cells (NK8+) associated with favourable outcome. NK8+ are capable of regulating CD4+ T cell activation and proliferation in vitro, with reduced expression of HLA-G binding inhibitory receptors and consequent reduced sensitivity to HLA-G-mediated suppression. We identify surrogate markers of the NK8+ signature in peripheral blood leucocytes and validate their association with clinical outcome in an independent cohort, suggesting their measurement may facilitate early, targeted therapy in RRMS.
Killer Cells, Natural, CD8-Positive T-Lymphocytes, Humans, Multiple Sclerosis, Relapsing-Remitting, Treatment Outcome, Risk Factors, Reproducibility of Results, Lymphocyte Activation, Gene Expression Regulation, Gene Regulatory Networks, HLA-G Antigens, Transcriptome
This work is supported by National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) and funded by a Medical Research Council (UK) programme award (MR/L019027). E.M. was a Wellcome –Beit Research Fellow supported by the Wellcome Trust and Beit Foundation (104064/Z/14/Z). K.G.C.S was a Lister Prize Fellow. We thank Anna Petrunkina-Harrison and Natalia Savinykh at the NIHR Cambridge Biomedical Research Cell Phenotyping Hub for extensive assistance. The authors also thank their colleagues at the Immune Tolerance Network, and their collaborators who contribute in many capacities to Immune Tolerance Network projects and perspectives. The authors are grateful to the ITN020AI STAyCIS study participants, and thank the clinical site investigators and study coordinators. Research reported in this publication was supported by the Immune Tolerance Network and sponsored by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1AI109565. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the NIHR or the Department of Health. The STAyCIS clinical trial was performed as a project of the Immune Tolerance Network (ITN020AI, ITN contract number N01-AI-15416) within a clinical research consortium sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).
WELLCOME TRUST (104064/Z/14/Z)
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External DOI: https://doi.org/10.1038/s41467-020-20594-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/313368
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