Dataset Information

Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation.

ABSTRACT: NK cells represent a critical first-line of immune defense against a bevy of viral pathogens, and infection can provoke them to mediate supportive and suppressive effects on virus-specific adaptive immunity. In mice expressing MHC class I Dk (Dk), a major murine CMV (MCMV) resistance factor and self-ligand of the inhibitory Ly49G2 (G2) receptor, licensed G2+ NK cells provide essential host resistance against MCMV infection. Additionally G2+ NK cell responses to MCMV increase the rate and extent of dendritic cell (DC) recovery, as well as early priming of CD8+ T cell effectors in response to MCMV. However, relatively little is known about the NK cell effect on costimulatory ligand patterns displayed by DCs or on ensuing effector and memory T cell responses. In this study, we found that CD27-dependent CD8+ T cell priming and differentiation are shaped by the efficiency of NK responses to virus infection. Surprisingly, differences in specific NK responses to MCMV in Dk-disparate mice failed to distinguish early DC costimulatory patterns. Nonetheless, although CD27 deficiency did not impede licensed NK-mediated resistance, CD70 and CD27 were required to efficiently prime and regulate effector CD8+ T cell differentiation in response to MCMV, which eventually resulted in biased memory T cell precursor formation in Dk mice. In contrast, CD8+ T cells accrued more slowly in non-Dk mice and eventually differentiated into terminal effector cells regardless of CD27 stimulation. Disparity in this requirement for CD27 signaling indicates that specific virus control mediated by NK cells can shape DC costimulatory signals needed to prime CD8+ T cells and eventual T cell fate decisions.

SUBMITTER: Teoh JJ

PROVIDER: S-EPMC5123769 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation.

Teoh Jeffrey J JJ Gamache Awndre E AE Gillespie Alyssa L AL Stadnisky Michael D MD Yagita Hideo H Bullock Timothy N J TN Brown Michael G MG

Journal of immunology (Baltimore, Md. : 1950) 20161024 11

NK cells represent a critical first-line of immune defense against a bevy of viral pathogens, and infection can provoke them to mediate supportive and suppressive effects on virus-specific adaptive immunity. In mice expressing MHC class I Dk (Dk), a major murine CMV (MCMV) resistance factor and self-ligand of the inhibitory Ly49G2 (G2) receptor, licensed G2+ NK cells provide essential host resistance against MCMV infection. Additionally G2+ NK cell res ...[more]

PMID: 27798162

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Project description:Clinical targeting of TNFR family of receptors (CD40, CD134 and CD137) with immunostimulatory monoclonal antibodies has been successful in cancer immunotherapy. However, targeting of CD27 with a mAb is a relatively new approach to provide costimulation of immune cells undergoing activation. Thus, activation of human CD27 (TNFRSF7) with a monoclonal antibody (varlilumab) has previously been demonstrated to result in T cell activation and anti-tumor activity in preclinical models, and is currently in early phase clinical trials in patients with advanced malignancies. In this study we used an in vitro system using human peripheral blood T cells to characterize the varlilumab-mediated costimulatory effects in combination with TCR stimulation in terms of phenotypic, transcriptional and functionality changes.T cells were isolated from normal volunteer PBMCs using magnetic bead isolation kits and stimulated in vitro with plate bound anti-CD3 Ab (OKT3) and varlilumab or control Ab for 72 h. Activation profiles were monitored by ELISA or Luminex-based testing cytokine/chemokine releases, cell surface phenotyping for costimulatory and coinhibitory markers and CFSE dye dilution by proliferating T cells and Tregs. Changes in gene expression and transcriptome analysis of varlilumab-stimulated T cells was carried on Agilent Human whole genome microarray datasets using a suite of statistical and bioinformatic software tools.Costimulation of T cells with varlilumab required continuous TCR signaling as pre-activated T cells were unable to produce cytokines with CD27 signaling alone. Analysis of T cell subsets further revealed that memory CD4+ and CD8+ T cells were specifically activated with a bias toward CD8+ T lymphocyte proliferation. Activation was accompanied by upregulated cell surface expression of costimulatory [4-1BB, OX40, GITR and ICOS] and coinhibitory [PD-1] molecules. Importantly, varlilumab costimulation did not activate purified Tregs as measured by cytokine production, proliferation and suppression of dividing non-Treg T cells. Analysis of changes in gene expression during varlilumab stimulation of T cells revealed modulation of pro-inflammatory signatures consistent with cellular activation and proliferation, with the IL-2 pathway showing the highest frequency of gene modulation.Altogether, the data reveal the requirements and T cell subtype-specific effects of CD27 costimulation, and helps select relevant biomarkers for studying the effects of varlilumab in patients.

Dataset Information

Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation.

Publications

Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation.

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