Lung injury induces a polarized immune response by self-antigen-specific CD4 Foxp3 regulatory T cells.

Self-antigen-specific T cells are prevalent in the mature adaptive immune system but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may allow these T cells to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self-antigen under highly stimulatory conditions, we use peptide:major histocompatibility complex (MHC) class II tetramers to track the behavior of endogenous CD4 T cells with specificity to a lung-expressed self-antigen in mouse models of immune-mediated lung injury.

A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma.

Asthma is a chronic disease most commonly associated with allergy and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, we compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing.

Lung injury induces a polarized immune response by self antigen-specific Foxp3 regulatory T cells.

Self antigen-specific T cells are prevalent in the mature adaptive immune system, but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may provide these T cells with an opportunity to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self antigen under highly stimulatory conditions, we used peptide:MHCII tetramers to track the behavior of endogenous CD4 T cells with specificity to a lung-expressed self antigen in mouse models of immune-mediated lung injury.

Functional Recognition Theory and Type 2 Immunity: Insights and Uncertainties.

Type 2 immunity plays an important role in host defense against helminths and toxins while driving allergic diseases. Despite progress in understanding the biology of type 2 immunity, the fundamental mechanisms regulating the type 2 immune module remain unclear. In contrast with structural recognition used by pattern recognition receptors, type 2 immunogens are sensed through their functional properties.

Advancing Lung Immunology Research: An Official American Thoracic Society Workshop Report.

The mammalian airways and lungs are exposed to a myriad of inhaled particulate matter, allergens, and pathogens. The immune system plays an essential role in protecting the host from respiratory pathogens, but a dysregulated immune response during respiratory infection can impair pathogen clearance and lead to immunopathology. Furthermore, inappropriate immunity to inhaled antigens can lead to pulmonary diseases.

Interleukin-33 activates regulatory T cells to suppress innate γδ T cell responses in the lung.

Foxp3 regulatory T (T) cells expressing the interleukin (IL)-33 receptor ST2 mediate tissue repair in response to IL-33. Whether T cells also respond to the alarmin IL-33 to regulate specific aspects of the immune response is not known. Here we describe an unexpected function of ST2 T cells in suppressing the innate immune response in the lung to environmental allergens without altering the adaptive immune response.

Redefining Memory T Cell Subsets.

It has become increasingly clear that the terms used to define memory T cell subsets no longer accurately reflect our understanding of memory T cell biology. Here, we discuss the limitations of our current terminology and propose a new approach for defining memory T cell subsets.

Distinct functions of tissue-resident and circulating memory Th2 cells in allergic airway disease.

Memory CD4+ T helper type 2 (Th2) cells drive allergic asthma, yet the mechanisms whereby tissue-resident memory Th2 (Th2 Trm) cells and circulating memory Th2 cells collaborate in vivo remain unclear. Using a house dust mite (HDM) model of allergic asthma and parabiosis, we demonstrate that Th2 Trm cells and circulating memory Th2 cells perform nonredundant functions. Upon HDM rechallenge, circulating memory Th2 cells trafficked into the lung parenchyma and ignited perivascular inflammation to promote eosinophil and CD4+ T cell recruitment.

Migratory DCs activate TGF-β to precondition naïve CD8 T cells for tissue-resident memory fate.

Epithelial resident memory T (eT) cells serve as sentinels in barrier tissues to guard against previously encountered pathogens. How eT cells are generated has important implications for efforts to elicit their formation through vaccination or prevent it in autoimmune disease. Here, we show that during immune homeostasis, the cytokine transforming growth factor β (TGF-β) epigenetically conditions resting naïve CD8 T cells and prepares them for the formation of eT cells in a mouse model of skin vaccination.

Dectin-2-induced CCL2 production in tissue-resident macrophages ignites cardiac arteritis.

Environmental triggers, including those from pathogens, are thought to play an important role in triggering autoimmune diseases, such as vasculitis, in genetically susceptible individuals. The mechanism by which activation of the innate immune system contributes to vessel-specific autoimmunity in vasculitis is not known. Systemic administration of Candida albicans water-soluble extract (CAWS) induces vasculitis in the aortic root and coronary arteries of mice that mimics human Kawasaki disease.

Chemokines: Critical Regulators of Memory T Cell Development, Maintenance, and Function.

Memory T cells are central to orchestrating antigen-specific recall responses in vivo. Compared to naïve T cells, memory T cells respond more quickly to cognate peptide:MHC with a shorter lag time for entering the cell cycle and exerting effector functions. However, it is now well established that this enhanced responsiveness is not the only mechanism whereby memory T cells are better equipped than naïve T cells to rapidly and robustly induce inflammation.

Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis.

Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells. Mitochondria in activated myofibroblasts, but not quiescent fibroblasts, are primed by death signals such as the proapoptotic BH3-only protein BIM, which creates a requirement for tonic expression of the antiapoptotic protein BCL-X to sequester BIM and ensure myofibroblast survival.

Physical rehabilitation of patients in the intensive care unit requiring extracorporeal membrane oxygenation: a small case series.

Background And Purpose: Neuromuscular weakness and impaired physical function are common and long-lasting complications experienced by intensive care unit (ICU) survivors. There is growing evidence that implementing rehabilitation therapy shortly after ICU admission improves physical function and reduces health care utilization. Recently, there is increasing interest and utilization of extracorporeal membrane oxygenation (ECMO) to support patients with severe respiratory failure.

ERBB receptor activation is required for profibrotic responses to transforming growth factor beta.

Engagement of the transforming growth factor-β (TGF-β) receptor complex activates multiple signaling pathways that play crucial roles in both health and disease. TGF-β is a key regulator of fibrogenesis and cancer-associated desmoplasia; however, its exact mode of action in these pathologic processes has remained poorly defined. Here, we report a novel mechanism whereby signaling via members of the ERBB or epidermal growth factor family of receptors serves as a central requirement for the biological responses of fibroblasts to TGF-β.

Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta.

Transforming growth factor-beta (TGF-beta) promotes a multitude of diverse biological processes, including growth arrest of epithelial cells and proliferation of fibroblasts. Although the TGF-beta signaling pathways that promote inhibition of epithelial cell growth are well characterized, less is known about the mechanisms mediating the positive response to this growth factor. Given that TGF-beta has been shown to promote fibrotic diseases and desmoplasia, identifying the fibroblast-specific TGF-beta signaling pathways is critical.

Lamprey snail highlights conserved and novel patterning roles in vertebrate embryos.

snail genes mark presumptive mesoderm across bilaterian animals. In gnathostome vertebrates, snail genes are a multimember family that are also markers of premigratory neural crest (pnc) and some postmigratory neural crest derivatives in the pharyngeal arches. Previous studies of nonvertebrate chordates indicate that they have single snail genes that retain ancestral functions in mesoderm development and perhaps in specification of a pnc-like cell population.

TGF-beta signaling: a tale of two responses.

Transforming growth factor-beta (TGF-beta) regulates a wide variety of cellular processes including cell growth, apoptosis, differentiation, migration, and extracellular matrix production among others. The canonical signaling pathway induced by the TGF-beta receptor complex involves the phosphorylation of Smad proteins which upon activation accumulate in the nucleus and regulate transcription. Interestingly, the cellular response to TGF-beta can be extremely variable depending on the cell type and stimulation context.

Methylmercury induces apoptosis in cultured rat dorsal root ganglion neurons.

Methylmercury is known to have devastating effects on the mammalian nervous system. In order to characterize the dose dependence of methylmercury-induced neurotoxicity, we first studied neurite outgrowth from rat dorsal root ganglia explants. In this model, methylmercury inhibited neurite outgrowth with a TD(50) of approximately 0.