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A CD8⁺ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis.

ABSTRACT: 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.

SUBMITTER: McKinney EF

PROVIDER: S-EPMC7840761 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A CD8<sup>+</sup> NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis.

McKinney Eoin F EF Cuthbertson Iona I Harris Kristina M KM Smilek Dawn E DE Connor Christopher C Manferrari Giulia G Carr Edward J EJ Zamvil Scott S SS Smith Kenneth G C KGC

Nature communications 20210127 1

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-generat ...[more]

PMID: 33504809

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Project description:ObjectiveTo characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures.MethodsThe project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment. T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed. Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked.ResultsVariable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types. Evidence of increased Treg competence was observed after each treatment course. CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells. Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk. In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells.ConclusionsLymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments. Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types. Several immune measures were identified as possible biomarkers of lesion activity. Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS.Trial registrationParent trials for this study are registered with ClinicalTrials.gov: CARE-MS II: NCT00548405, CARE-MS II extension: NCT00930553 and ISS: NCT01307332.

Dataset Information

A CD8⁺ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis.

Publications

A CD8<sup>+</sup> NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis.

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Dataset Information

A CD8+ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis.

Publications

A CD8<sup>+</sup> NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A CD8⁺ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis.