Amit K. Mehta

Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production.

BACKGROUND Cysteinyl leukotrienes (CysLTs) contribute to asthma pathogenesis, in part through cysteinyl leukotriene receptor 1 (CysLT1R). Recently discovered lineage-negative type 2 innate lymphoid cells (ILC2s) potently produce IL-5 and IL-13. OBJECTIVES We hypothesized that lung ILC2s might be activated by leukotrienes through CysLT1R. METHODS ILC2s (Thy1.2(+) lineage-negative lymphocytes) and CysLT1R were detected in the lungs of wild-type, signal transducer and activator of transcription 6-deficient (STAT6(-/-)), and recombination-activating gene 2-deficient (RAG2(-/-)) mice by means of flow cytometry. T(H)2 cytokine levels were measured in purified lung ILC2s stimulated with leukotriene D₄ (LTD₄) in the presence or absence of the CysLT1R antagonist montelukast. Calcium influx was measured by using Fluo-4 intensity. Intranasal leukotriene C₄, D₄, and E₄ were administered to naive mice, and levels of ILC2 IL-5 production were determined. Finally, LTD₄ was coadministered with Alternaria species repetitively to RAG2(-/-) mice (with ILC2s) and IL-7 receptor-deficient mice (lack ILC2s), and total ILC2 numbers, proliferation (Ki-67(+)), and bronchoalveolar lavage fluid eosinophil numbers were measured. RESULTS CysLT1R was expressed on lung ILC2s from wild-type, RAG2(-/-), and STAT6(-/-) naive and Alternaria species-challenged mice. In vitro LTD₄ induced ILC2s to rapidly generate high levels of IL-5 and IL-13 within 6 hours of stimulation. Interestingly, LTD4, but not IL-33, induced high levels of IL-4 by ILC2s. LTD₄ administered in vivo rapidly induced ILC2 IL-5 production that was significantly reduced by montelukast before treatment. Finally, LTD₄ potentiated Alternaria species-induced eosinophilia, as well as ILC2 accumulation and proliferation. CONCLUSIONS We present novel data that CysLT1R is expressed on ILC2s and LTD₄ potently induces CysLT1R-dependent ILC2 production of IL-4, IL-5, and IL-13. Additionally, LTD₄ potentiates Alternaria species-induced eosinophilia and ILC2 proliferation and accumulation.

Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance

Lung-resident antigen-presenting macrophages promote tolerance to inhaled antigens via the induction of regulatory T cells.

TNF superfamily in inflammatory disease: translating basic insights

The tumor necrosis factor (TNF) and TNF receptor superfamilies (TNFSF and TNFRSF) consist of approximately 50 membrane and soluble proteins that can modulate cellular function. Most of these molecules are expressed by or can target cells of the immune system, and they have a wide range of actions including promoting cellular differentiation, survival, and production of inflammatory cytokines and chemokines. Emerging data show that TNFSF ligand-receptor signaling pathways are active in inflammatory and autoimmune disease. Furthermore, several genetic polymorphisms in TNFSF and TNFRSF associate with susceptibility to developing disease. Here, we examine recent data regarding the potential of these molecules as targets for therapy of autoimmune and inflammatory disease.

Innate signals from Nod2 block respiratory tolerance and program TH2-driven allergic inflammation

BACKGROUND Airway tolerance is critical for protecting the lung from inflammatory disease driven by allergens. However, factors that disrupt tolerance processes and then lead to susceptibility to developing allergic asthma remain elusive. OBJECTIVE To investigate whether recognition of bacterial microbial-associated molecular patterns in the lung may result in susceptibility to developing allergic reactions, and to understand the molecular mechanisms by which such triggers block natural tolerance. METHODS Ligands of intracellular microbial-associated molecular pattern recognition receptors-the nucleotide-binding oligomerization domain (Nod)-like receptors, Nod1 and Nod2-were given intranasally with antigen, and their ability to modulate airway tolerance was analyzed. RESULTS Intranasal Nod2 ligand rapidly induced lung expression of the innate cytokines thymic stromal lymphopoietin and IL-25, and thymic stromal lymphopoietin promoted expression of OX40 ligand, a T-cell-costimulatory ligand, on lung CD11c(+)CD11b(+) cells and B220(+) cells. Together these 3 molecules blocked the generation of antigen-specific CD4(+)forkhead box protein 3(+) adaptive regulatory T cells and concomitantly drove IL-4-producing CD4 T cells. By altering the regulatory T/T(H)2-cell balance, tolerance was blocked, and sensing of Nod2 ligand resulted in subsequent susceptibility to developing eosinophil-dominated airway inflammation. CONCLUSION We show that a Nod-like receptor is a novel, previously unrecognized, pathway that adversely links innate and adaptive immunity and leads to allergic disease and asthmatic lung inflammation.

Galectin-9 controls the therapeutic activity of 4-1BB–targeting antibodies

Agonistic anti–4-1BB suppresses autoimmune and allergic inflammation via binding to Galectin-9, which facilitates 4-1BB aggregation, signaling, and functional activity.

Inducible CD4+LAP+Foxp3− Regulatory T Cells Suppress Allergic Inflammation

Regulatory T cells (Tregs) play a critical role in the maintenance of airway tolerance. We report that inhaled soluble Ag induces adaptive Foxp3+ Tregs, as well as a regulatory population of CD4+ T cells in the lungs and lung-draining lymph nodes that express latency-associated peptide (LAP) on their cell surface but do not express Foxp3. Blocking the cytokine IL-10 or TGF-β prevented the generation of LAP+ Tregs and Foxp3+ Tregs in vivo, and the LAP+ Tregs could also be generated concomitantly with Foxp3+ Tregs in vitro by culturing naive CD4+ T cells with Ag and exogenous TGF-β. The LAP+ Tregs strongly suppressed naive CD4+ T cell proliferation, and transfer of sorted OVA-specific LAP+ Tregs in vivo inhibited allergic eosinophilia and Th2 cytokine expression in the lung, either when present at the time of Th2 sensitization or when injected after Th2 cells were formed. Furthermore, inflammatory innate stimuli from house dust mite extract, nucleotide-binding oligomerization domain containing 2 ligand, and LPS, which are sufficient for blocking airway tolerance, strongly decreased the induction of LAP+ Tregs. Taken together, we concluded that inducible Ag-specific LAP+ Tregs can suppress asthmatic lung inflammation and constitute a mediator of airway tolerance together with Foxp3+ Tregs.

Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations

Blocking HVEM–LIGHT interactions on T cells reduces the persistence of antigen-specific memory T cell populations after secondary expansion through decreased Akt activity and loss of Bcl-2 expression.

Leukotriene C4 Potentiates IL-33–Induced Group 2 Innate Lymphoid Cell Activation and Lung Inflammation

Asthma is a complex disease that is promoted by dysregulated immunity and the presence of many cytokine and lipid mediators. Despite this, there is a paucity of data demonstrating the combined effects of multiple mediators in asthma pathogenesis. Group 2 innate lymphoid cells (ILC2s) have recently been shown to play important roles in the initiation of allergic inflammation; however, it is unclear whether lipid mediators, such as cysteinyl leukotrienes (CysLTs), which are present in asthma, could further amplify the effects of IL-33 on ILC2 activation and lung inflammation. In this article, we show that airway challenges with the parent CysLT, leukotriene C4 (LTC4), given in combination with low-dose IL-33 to naive wild-type mice, led to synergistic increases in airway Th2 cytokines, eosinophilia, and peribronchial inflammation compared with IL-33 alone. Further, the numbers of proliferating and cytokine-producing lung ILC2s were increased after challenge with both LTC4 and IL-33. Levels of CysLT1R, CysLT2R, and candidate leukotriene E4 receptor P2Y12 mRNAs were increased in ILC2s. The synergistic effect of LTC4 with IL-33 was completely dependent upon CysLT1R, because CysLT1R−/− mice, but not CysLT2R−/− mice, had abrogated responses. Further, CysLTs directly potentiated IL-5 and IL-13 production from purified ILC2s stimulated with IL-33 and resulted in NFAT1 nuclear translocation. Finally, CysLT1R−/− mice had reduced lung eosinophils and ILC2 responses after exposure to the fungal allergen Alternaria alternata. Thus, CysLT1R promotes LTC4- and Alternaria-induced ILC2 activation and lung inflammation. These findings suggest that multiple pathways likely exist in asthma to activate ILC2s and propagate inflammatory responses.

TNF activity and T cells.

TNF (tumor necrosis factor) is both a pro-inflammatory and anti-inflammatory cytokine that is central to the development of autoimmune disease, cancer, and protection against infectious pathogens. As well as a myriad other activities, TNF can be a product of T cells and can act on T cells. Here we review old and new data on the importance of TNF produced by T cells and how TNF signaling via TNFR2 may directly impact alternate aspects of T cell biology. TNF can promote the activation and proliferation of naïve and effector T cells, but also can induce apoptosis of highly activated effector T cells, further determining the size of the pathogenic or protective conventional T cell pool. Moreover, TNF can have divergent effects on regulatory T cells. It can both downregulate their suppressive capacity, but also contribute in other instances to their development or accumulation. Biologics that block TNF or stimulate TNFR2 therefore have the potential to strongly modulate the balance between effector T cells and Treg cells which could impact disease in both positive and negative manners.

Rhinovirus Infection of ORMDL3 Transgenic Mice Is Associated with Reduced Rhinovirus Viral Load and Airway Inflammation

Orosomucoid like 3 (ORMDL3), a gene localized to chromosome 17q21, has been linked in epidemiologic studies to childhood asthma and rhinovirus (RV) infections. As the single nucleotide polymorphisms linking ORMDL3 to asthma are associated with increased expression of ORMDL3, we have used hORMDL3zp3-Cre mice (which have universal increased expression of human ORMDL3) to determine whether infection of these transgenic mice with RV influences levels of airway inflammation or RV viral load. RV infection of hORMDL3zp3-Cre mice resulted in reduced RV viral load assessed by quantitative real-time PCR (lung and airway epithelium), as well as reduced airway inflammation (total bronchoalveolar lavage cells, neutrophils, macrophages, and lymphocytes) compared with RV-infected wild-type mice. Levels of the antiviral pathways including IFNs (IFN-α, IFN-β, IFN-λ) and RNAse L were significantly increased in the lungs of RV-infected hORMDL3zp3-Cre mice. Levels of the antiviral mouse oligoadenylate synthetase (mOas)1g pathway and RNAse L were upregulated in the lungs of unchallenged hORMDL3zp3-Cre mice. In addition, levels of mOas2, but not mOas1 (mOas1a, mOas1b, mOas1g), or mOas3 pathways were significantly more upregulated by IFNs (IFN-α, IFN-β, IFN-λ) in epithelial cells from hORMDL3zp3-Cre mice compared with RV-infected wild-type mouse epithelial cells. RNAse L–deficient mice infected with RV had increased RV viral load. Overall, these studies suggest that increased levels of ORMDL3 contribute to antiviral defense to RV infection in mice through pathways that may include IFNs (IFN-α, IFN-β, IFN-λ), OAS, and RNAse L.