Dataset Information

Human IL-6RhiTIGIT- CD4+CD127lowCD25+ T cells display potent in vitro suppressive capacity and a distinct Th17 profile.

ABSTRACT: To date many clinical studies aim to increase the number and/or fitness of CD4+CD127lowCD25+ regulatory T cells (Tregs) in vivo to harness their regulatory potential in the context of treating autoimmune disease. Here, we sought to define the phenotype and function of Tregs expressing the highest levels of IL-6 receptor (IL-6R). We have identified a population of CD4+CD127lowCD25+ TIGIT- T cells distinguished by their elevated IL-6R expression that lacked expression of HELIOS, showed higher CTLA-4 expression, and displayed increased suppressive capacity compared to IL-6RhiTIGIT+ Tregs. IL-6RhiTIGIT- CD127lowCD25+ T cells contained a majority of cells demethylated at FOXP3 and displayed a Th17 transcriptional signature, including RORC (ROR?t) and the capacity of producing both pro- and anti-inflammatory cytokines, such as IL-17, IL-22 and IL-10. We propose that in vivo, in the presence of IL-6-associated inflammation, the suppressive function of CD4+CD127lowCD25+ FOXP3+IL-6RhiTIGIT- T cells is temporarily disarmed allowing further activation of the effector functions and potential pathogenic tissue damage.

SUBMITTER: Ferreira RC

PROVIDER: S-EPMC5471606 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Human IL-6RhiTIGIT- CD4+CD127lowCD25+ T cells display potent in vitro suppressive capacity and a distinct Th17 profile.

Ferreira Ricardo C RC Rainbow Daniel B DB Rubio García Arcadio A Pekalski Marcin L ML Porter Linsey L Oliveira João J JJ Waldron-Lynch Frank F Wicker Linda S LS Todd John A JA

Clinical immunology (Orlando, Fla.) 20170309

To date many clinical studies aim to increase the number and/or fitness of CD4+CD127lowCD25+ regulatory T cells (Tregs) in vivo to harness their regulatory potential in the context of treating autoimmune disease. Here, we sought to define the phenotype and function of Tregs expressing the highest levels of IL-6 receptor (IL-6R). We have identified a population of CD4+CD127lowCD25+ TIGIT- T cells distinguished by their e ...[more]

PMID: 28284938

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Project description:The CNS has traditionally been considered an immune privileged site, but is now understood to have a system of immune surveillance, predominantly involving CD4+ T-cells. Identifying functional differences between CNS and blood CD4+ T-cells, therefore, have relevance to CNS immune surveillance as well as to neurological conditions, such as multiple sclerosis, in which CD4+ T-cells play a central role. Here, CD4+ T-cells were purified from CSF and blood from 21 patients with newly diagnosed treatment-naïve multiple sclerosis and 20 individuals with non-inflammatory disorders using fluorescence-activated cell sorting, and their transcriptomes were profiled by RNA sequencing. Paired comparisons between CD4+ T-cells from CSF and blood identified 5156 differentially expressed genes in controls and 4263 differentially expressed in multiple sclerosis patients at false discovery rate <5%. Differential expression analysis of CD4+ T-cells collected from the CSF highlighted genes involved in migration, activation, cholesterol biosynthesis and signalling, including those with known relevance to multiple sclerosis pathogenesis and treatment. Expression of markers of CD4+ T-cell subtypes suggested an increased proportion of Th1 and Th17 cells in CSF. Gene ontology terms significant only in multiple sclerosis were predominantly those involved in cellular proliferation. A two-way comparison of CSF versus blood CD4+ T-cells in multiple sclerosis compared with non-inflammatory disorder controls identified four significant genes at false discovery rate <5% (CYP51A1, LRRD1, YES1 and PASK), further implicating cholesterol biosynthesis and migration mechanisms. Analysis of CSF CD4+ T-cells in an extended cohort of multiple sclerosis cases (total N = 41) compared with non-inflammatory disorder controls (total N = 38) identified 140 differentially expressed genes at false discovery rate < 5%, many of which have known relevance to multiple sclerosis, including XBP1, BHLHE40, CD40LG, DPP4 and ITGB1. This study provides the largest transcriptomic analysis of purified cell subpopulations in CSF to date and has relevance for the understanding of CNS immune surveillance, as well as multiple sclerosis pathogenesis and treatment discovery.

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Dataset Information

Human IL-6RhiTIGIT- CD4+CD127lowCD25+ T cells display potent in vitro suppressive capacity and a distinct Th17 profile.

Publications

Human IL-6R<sup>hi</sup>TIGIT<sup>-</sup> CD4<sup>+</sup>CD127<sup>low</sup>CD25<sup>+</sup> T cells display potent in vitro suppressive capacity and a distinct Th17 profile.

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