Graphene oxide polarizes iNKT cells for production of TGF\u03b2 and attenuates inflammation in an iNKT cell-mediated sepsis model

Sung Won Lee,Seokmann Hong,Suklyun Hong,Luc Van Kaer,Hyun Jung Park

doi:10.1038/s41598-018-28396-9

Sung Won Lee, Seokmann Hong + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-28396-9

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Journal: Scientific Reports	Publication Date: Jul 4, 2018
Citations: 29	License type: open-access

Affiliation: Sejong University, Vanderbilt University

Abstract

Graphene oxide (GO) modulates the functions of antigen-presenting cells including dendritic cells (DCs). Although carbon nanotubes affect expression of the MHC class I-like CD1d molecule, whether GO can influence immune responses of CD1d-dependent invariant natural killer T (iNKT) cells remains unclear. Here, we investigated the impact of GO on inflammatory responses mediated by α-galactosylceramide (α-GalCer), an iNKT cell agonist. We found that in vivo GO treatment substantially inhibited the capacity of α-GalCer to induce the iNKT cell-mediated trans-activation of and cytokine production by innate and innate-like cells, including DCs, macrophages, NK cells, and γδ T cells. Such effects of GO on α-GalCer-induced inflammatory responses closely correlated with iNKT cell polarization towards TGFβ production, which also explains the capacity of GO to expand regulatory T cells. Interestingly, the absence of TLR4, a receptor for GO, failed to downregulate, and instead partially enhanced the anti-inflammatory activity of GO against α-GalCer-elicited responses, implying negative effects of TLR4 signaling on the anti-inflammatory properties of GO. By employing an α-GalCer-induced sepsis model, we further demonstrated that GO treatment significantly protected mice from α-GalCer-induced lethality. Taken together, we provide strong evidence that GO holds promise as an adjuvant to modulate iNKT cell responses for immunotherapy.

Highlights

Sepsis, known as a systemic inflammatory response syndrome (SIRS), is a life-threatening illness triggered by the systemic release of microbial products during infection
We investigated whether Graphene oxide (GO) can modulate immune responses using a model of invariant natural killer T (iNKT) cell activation with α-GalCer
Previous studies have reported that GO interacts with APCs such as DCs and macrophages, and that GO downregulates CD1d expression on DCs12,25, its effects on iNKT cells have remained unexplored

Summary

Introduction

Known as a systemic inflammatory response syndrome (SIRS), is a life-threatening illness triggered by the systemic release of microbial products during infection. Stimulation of iNKT cells in response to co-administration of either α-GalCer plus D-galactosamine (D-GalN)[8] or α-GalCer plus LPS9 in mice induces liver injury through IFNγ and TNFα production, resulting in www.nature.com/scientificreports/. The majority of studies on graphene-family nanomaterials have focused on cytotoxic effects against immune cells[11] These studies revealed GO-mediated necrotic cell death of macrophages via TLR4 signaling and autocrine TNFα production[12]. We report that GO treatment significantly inhibits pro-inflammatory cytokine production in response to iNKT cell activation by α-GalCer, which involved modulation of both CD1d-mediated antigen presentation and iNKT cell responses. The immunomodulatory effects of GO on α-GalCer-mediated immune responses involved polarization of iNKT cell responses from IL4/IFNγ production towards TGFβ production, which subsequently led to an expansion of regulatory T (Treg) cells. These findings highlight GO as an excellent drug delivery carrier for treatment of septic shock

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