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.

The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

“…In particular, it is necessary to better characterize both the virological and immunological aspects of EBV infection in MS patients. At the clinical level, cytotoxic immune cell subsets could be valid biomarkers of treatment efficacy, as indicated by a recent study showing that expansion of CD8+ NK cells in the peripheral blood of MS patients is associated with reduced relapse risk ( 65 ). It is foreseen that integration of single cell technologies, like single cell transcriptomics and multiparameter spectral flow cytometry, will soon provide a comprehensive and accurate picture of disease relevant immune cell subsets in the CSF and peripheral blood of MS patients, allowing to monitor their frequency and function during treatment.…”

“…An interaction between EBV infection and HLA genes associated with MS risk is suggested by the finding that HLA-DRB1*15 carriers with higher anti-EBNA-1 antibody titers have a markedly elevated risk of MS (102)(103)(104), which is increased further in the absence of the protective allele HLA-A*0201 (103). (65), raising the possibility that this cell subset is involved in the control of EBV infection.…”

Systems analysis of immune responses to attenuated P. falciparum malaria sporozoite vaccination reveals excessive inflammatory signatures correlating with impaired immunity

“…However CD8-expressing NK cells subsets did not show any early peak in P participants. Notably, CD8+ NK cells lacking FcRγ were more abundant in NP subjects across all measured timepoints (Hart et al, 2019; Hwang et al, 2012; McKinney et al, 2021; Zambello et al, 2020).…”

“…The copyright holder for this preprint (which this version posted July 29, 2021. ; https://doi.org/10.1101/2021.07.28.454252 doi: bioRxiv preprint subjects across all measured timepoints (Hart et al, 2019;Hwang et al, 2012;McKinney et al, 2021;Zambello et al, 2020).…”

Proportions of circulating transitional B cells associate with MRI activity in interferon beta-treated multiple sclerosis patients

“…[1] Although the exact underlying disease mechanisms of MS are not yet fully elucidated, several lymphocyte populations have been associated with its disease process. These include T helper 1 cells (CD4 + IFN-γ + T cell, Th1 cell), [2] T helper 17 cells (IL-17A + CD4 + T cell, Th17 cell) [3,4], J o u r n a l P r e -p r o o f natural killer (NK) cells [5][6][7], and B cells [8,9]. Several environmental factors associated with MS onset are believed to modulate the functional or phenotypic characteristics of these lymphocytes, including vitamin D levels, [10][11][12] infection with Epstein-Barr virus (EBV), [13][14][15] smoking [16] and obesity.…”