Chauche, C. | Search bioRxiv

bioRxiv2024

Epithelial memory after respiratory viral infection results in long-lasting enhancement of antigen presentation

BackgroundViral lower respiratory tract infections (LRTIs) can reduce severity of subsequent LRTIs but have also been linked to respiratory allergy development and exacerbation. Here, we show that viral LRTI can imprint lung epithelial cells (LECs), leading to long-term phenotypic and functional changes in their response to subsequent challenges. MethodsMice were infected via intranasal administration of respiratory syncytial virus (RSV). After 28 days, LECs were isolated using cold dispase digestion followed by magnetic-activated cell sorting. Epigenetic changes were assessed using CUT&RUN, while transcriptional changes were evaluated using NanoString and qPCR. Flow cytometry was employed to measure cell surface MHC levels, antigen uptake and processing rates, and OT-I proliferation. ResultsWe identified epigenetic and transcriptomic changes in murine LECs 28 days post respiratory syncytial virus (RSV) infection after recovery in genes associated with major histocompatibility complexes (MHC). Lasting upregulation of MHC-I and MHC-II was further increased following in vivo LPS stimulation. Importantly, MHC upregulation was associated with increased antigen uptake and processing, as well as increased antigen presentation to T cells. ConclusionsOur data suggest that LRTI can induce long-term upregulation of antigen-presentation by LECs, thus facilitating local T cell responses to microbial antigens and allergens, potentially enhancing immunity or in susceptible hosts respiratory allergy.

immunology↗

bioRxiv2020

A truncated form of HpARI stabilises IL-33, amplifying responses to the cytokine.

1The murine intestinal nematode Heligmosomoides polygyrus releases the H. polygyrus Alarmin Release Inhibitor (HpARI) - a protein which binds to IL-33 and to DNA, effectively tethering the cytokine in the nucleus of necrotic cells. Previous work showed that a non-natural truncation consisting of the first 2 domains of HpARI (HpARI_CCP1/2) retains binding to both DNA and IL-33, and inhibited IL-33 release in vivo. Here, we show that the affinity of HpARI_CCP1/2 for IL-33 is significantly lower than that of the full-length protein, and that HpARI_CCP1/2 lacks the ability to prevent interaction of IL-33 with its receptor. When HpARI_CCP1/2 was applied in vivo it potently amplified IL-33-dependent immune responses to Alternaria alternata allergen, Nippostrongylus brasiliensis infection and recombinant IL-33 injection. Mechanistically, we found that HpARI_CCP1/2 is able to bind to and stabilise IL-33, preventing its degradation and maintaining the cytokine in its active form. This study highlights the importance of IL-33 inactivation, the potential for IL-33 stabilisation in vivo, and describes a new tool for IL-33 research.

immunology↗