Claire Mesnil

Lung-resident eosinophils represent a distinct regulatory eosinophil subset.

Increases in eosinophil numbers are associated with infection and allergic diseases, including asthma, but there is also evidence that eosinophils contribute to homeostatic immune processes. In mice, the normal lung contains resident eosinophils (rEos), but their function has not been characterized. Here, we have reported that steady-state pulmonary rEos are IL-5-independent parenchymal Siglec-FintCD62L+CD101lo cells with a ring-shaped nucleus. During house dust mite-induced airway allergy, rEos features remained unchanged, and rEos were accompanied by recruited inflammatory eosinophils (iEos), which were defined as IL-5-dependent peribronchial Siglec-FhiCD62L-CD101hi cells with a segmented nucleus. Gene expression analyses revealed a more regulatory profile for rEos than for iEos, and correspondingly, mice lacking lung rEos showed an increase in Th2 cell responses to inhaled allergens. Such elevation of Th2 responses was linked to the ability of rEos, but not iEos, to inhibit the maturation, and therefore the pro-Th2 function, of allergen-loaded DCs. Finally, we determined that the parenchymal rEos found in nonasthmatic human lungs (Siglec-8+CD62L+IL-3Rlo cells) were phenotypically distinct from the iEos isolated from the sputa of eosinophilic asthmatic patients (Siglec-8+CD62LloIL-3Rhi cells), suggesting that our findings in mice are relevant to humans. In conclusion, our data define lung rEos as a distinct eosinophil subset with key homeostatic functions.

Resident CD11b+Ly6C− Lung Dendritic Cells Are Responsible for Allergic Airway Sensitization to House Dust Mite in Mice

Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway sensitization. Here, we systematically assessed the respective pro-allergic potential of individually sorted lung DC subsets isolated from house dust mite antigen (HDM)-treated donor mice, following transfer to naïve recipients. Transfer of lung CD11c+CD11b+ DCs, but not CD11c+CD11b−CD103+ DCs, was sufficient to prime airway allergy. The CD11c+CD11b+ DC subpopulation was composed of CD11c+CD11b+Ly6C+ inflammatory monocyte-derived cells, whose numbers increase in the lungs following HDM exposure, and of CD11c+CD11b+Ly6C− DCs, which remain stable. Counterintuitively, only CD11c+CD11b+Ly6C− DCs, and not CD11c+CD11b+Ly6C+ DCs, were able to convey antigen to the lymph nodes and induce adaptive T cell responses and subsequent airway allergy. Our results thus support that lung resident non-inflammatory CD11c+CD11b+Ly6C− DCs are the essential inducers of allergic airway sensitization to the common aeroallergen HDM in mice.

Interferon response factor 3 is essential for house dust mite–induced airway allergy

BACKGROUND Pattern-recognition receptors (PRRs) are critically involved in the pathophysiology of airway allergy, yet most of the signaling pathways downstream of PRRs implicated in allergic airway sensitization remain unknown. OBJECTIVE We sought to study the effects of genetic depletion of interferon response factor (IRF) 3 and IRF7, important transcription factors downstream of various PRRs, in a murine model of house dust mite (HDM)-induced allergic asthma. METHODS We compared HDM-induced allergic immune responses in IRF3-deficient (IRF3(-/-)), IRF7(-/-), and wild-type mice. RESULTS Parameters of airway allergy caused by HDM exposure were strongly attenuated in IRF3(-/-), but not IRF7(-/-), mice compared with those in wild-type mice. Indeed, in HDM-exposed IRF3(-/-) mice HDM-specific T(H)2 cell responses did not develop. This correlated with impaired maturation and migration of IRF3(-/-) lung dendritic cells (DCs) on HDM treatment. Furthermore, adoptive transfer of HDM-loaded DCs indicated that IRF3(-/-) DCs had an intrinsic defect rendering them unable to migrate and to prime HDM-specific T(H)2 responses. Intriguingly, we also show that DC function and allergic airway sensitization in response to HDM were independent of signaling by type I interferons, the main target genes of IRF3. CONCLUSION Through its role in DC function, IRF3, mainly known as a central activator of antiviral immunity, is essential for the development of T(H)2-type responses to airway allergens.

A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes

The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the TH2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection.

Homeostatic Eosinophils: Characteristics and Functions

Eosinophils are typically considered to be specialized effector cells that are recruited to the tissues as a result of T helper type 2 (Th2) cell responses associated with helminth infections or allergic diseases such as asthma. Once at the site of injury, eosinophils release their cytotoxic granule proteins as well as preformed cytokines and lipid mediators, contributing to parasite destruction but also to exacerbation of inflammation and tissue damage. Accumulating evidence indicates that, besides their roles in Th2 responses, eosinophils also regulate homeostatic processes at steady state, thereby challenging the exclusive paradigm of the eosinophil as a destructive and inflammatory cell. Indeed, under baseline conditions, eosinophils rapidly leave the bloodstream to enter tissues, mainly the gastrointestinal tract, lungs, adipose tissue, thymus, uterus, and mammary glands, where they regulate a variety of important biological functions, such as immunoregulation, control of glucose homeostasis, protection against obesity, regulation of mammary gland development, and preparation of the uterus for pregnancy. This article provides an overview of the characteristics and functions of these homeostatic eosinophils.

Interferon response factor‐3 promotes the pro‐Th2 activity of mouse lung CD11b+ conventional dendritic cells in response to house dust mite allergens

Very few transcription factors have been identified that are required by antigen‐presenting cells (APCs) to induce T helper type 2 (Th2) responses. Because lung CD11b+ conventional dendritic cells (CD11b+ cDCs) are responsible for priming Th2 responses in house‐dust mite (HDM)‐induced airway allergy, we used them as a model to identify transcriptional events regulating the pro‐Th2 activity of cDCs. Transcriptomic profiling of lung CD11b+ cDCs exposed to HDM in vivo revealed first that HDM triggers an antiviral defence‐like response, and second that the majority of HDM‐induced transcriptional changes depend on the transcription factor Interferon Response Factor‐3 (Irf3). Validating the functional relevance of these observations, Irf3‐deficient CD11b+ cDCs displayed reduced pro‐allergic activity. Indeed, Irf3‐deficient CD11b+ cDCs induced less Th2, more regulatory T cell, and similar Th1 differentiation in naïve CD4+ T cells compared to their wild‐type counterparts. The altered APC activity of Irf3 CD11b+ cDCs was associated with reduced expression of CD86 and was phenocopied by blocking CD86 activity in wild‐type CD11b+ cDCs. Altogether, these results establish Irf3, known mostly for its role in antiviral responses, as a transcription factor involved in the induction of Th2 responses through the promotion of pro‐Th2 costimulation in CD11b+ DCs.

Viral induction of Zac1b through TLR3- and IRF3-dependent pathways

Zinc finger protein regulator of apoptosis and cell cycle arrest (Zac1) is a transcription factor able to induce apoptosis or cell cycle arrest through independent pathways. In spite of the important potential functions attributed to Zac1, little is known of its physiological regulation and biological function. We discovered that variant Zac1b was expressed in murine embryonic fibroblasts (MEFs) treated with polyriboinosinic polyribocytidylic acid [poly(I:C)], a synthetic double-stranded RNA. This regulation occurred mainly through Toll-Like Receptor 3 (TLR3)- and Interferon Regulatory Factor 3 (IRF3)-dependent pathways. As TLR3 and IRF3 are central activators of antiviral immunity, we hypothesized that Zac1 may be implicated in antiviral responses. In line with this notion, we observed that Zac1b was expressed in MEFs infected with Encephalomyocarditis virus (EMCV). We also observed that Zac1-deficient MEFs were less sensitive to EMCV-induced cell death than wild-type MEFs. However, Zac1 gene inactivation had no effect on the survival of mice infected with EMCV. In conclusion, this study describes for the first time a transcriptional regulation of Zac1b, induced by synthetic dsRNA and RNA viruses, the functional significance of which remains to be further investigated.

Author Correction: A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.

In the version of this article initially published, the accession code for the RNA-seq data set deposited in the NCBI public repository Sequence Read Archive was missing from the ‘Data availability’ subsection of the Methods section. The accession code is SRP125477.