IL-35 is critical in suppressing superantigenic Staphylococcus aureus-driven inflammatory Th17 responses in human nasopharynx-associated lymphoid tissue

Rong Xu,Rebecca K Shears,Aras Kadioglu,Christopher Webb,Richard Ali,Ravi Sharma,Madhan Krishna,Xiaoqing Wei,Qibo Zhang

doi:10.1038/s41385-019-0246-1

Abstract

The human nasopharynx is frequently exposed to microbial pathogens, including superantigen-producing Staphylococcus aureus (SAg-Sau), which activates potent pro-inflammatory T cell responses. However, cellular mechanisms that control SAg-Sau-driven T cell activation are poorly understood. Using human nasopharynx-associated lymphoid tissue (NALT), we show that SAg-Sau drove a strong Th17 activation, which was associated with an impaired CD4+ T cell-mediated immune regulation. This impairment of immune control correlated with a significant downregulation of interleukin-35 (IL-35) expression in tonsillar CD4+ T cells by SAg-Sau. Supplementing recombinant IL-35 suppressed SAg-Sau-activated Th17 responses, and this IL-35-mediated suppression positively correlated with the level of Th17 activation. Interestingly, SAg-Sau stimulation induced Foxp3+ Treg expansion and interleukin-10 (IL-10) production, which effectively suppressed the Th1 response, but failed to control the activation of Th17 cells. Overall, our results reveal an aberrant T cell regulation on SAg-Sau-driven Th17 activation and identify IL-35 as a critical cytokine to control superantigenic S.aureus-activated Th17 responses.

Highlights

Staphylococcus aureus (Sau) is a commonly identified bacterial colonizer of the nasopharyngeal mucosa in humans.[1]
superantigen-producing Staphylococcus aureus (SAg-Sau) activates a potent Th17 response in human tonsillar MNCs To examine whether SAg-Sau activates Th17 responses in human nasopharynx-associated lymphoid tissue (NALT), tonsillar mononuclear cells (MNCs) were stimulated with bacterial culture supernatant of Sau
Streptococcus pneumoniae (Spn) elicited a weak Th17 response, and no significant Th17 response was activated by M. catarrhalis and coagulase-negative staphylococcal strains (Fig. 1d)

Summary

Introduction

Staphylococcus aureus (Sau) is a commonly identified bacterial colonizer of the nasopharyngeal mucosa in humans.[1] Up to half of the Sau isolates are known to be superantigenic, and produce various superantigens, including toxic shock syndrome toxin (TSST) and staphylococcal enterotoxins (SEA, SEB, SEC, SED, and SEE).[2,3] These superantigens are extremely potent in stimulating poly-clonal T cell activation via cross-linking the MHC Class II of antigen-presenting cells (APC) and T cell receptor Vβ chain, which is not restricted to antigen specificity.[4]. Nasopharyngeal carriage of Sau increases the risk of invasive infections such as pneumonia, endocarditis and bacteraemia.[5] SAg-Sau infection could cause toxic shock through the release of superantigens which elicit potent T cell activation and a “cytokine storm”.6. SAg-Sau infection could cause toxic shock through the release of superantigens which elicit potent T cell activation and a “cytokine storm”.6 Further, SAg-Sau colonization has been associated with a range of inflammatory/autoimmune conditions, including asthma, chronic rhinosinusitis, Wegener’s granulomatosis (WG) and multiple sclerosis (MS).[3,7,8,9]

Methods

Results

Conclusion