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1.
Nature ; 634(8033): 440-446, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39232162

ABSTRACT

In naive individuals, sensory neurons directly detect and respond to allergens, leading to both the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response1,2. In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch3-7. Although these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naive state is unknown. Here we describe a γδ T cell-IL-3 signalling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal γδ T cell subset8, termed GD3 cells, that produces its hallmark cytokine IL-3 to promote allergic itch and the initiation of the allergic immune response. Mechanistically, IL-3 acts on Il3ra-expressing sensory neurons in a JAK2-dependent manner to lower their threshold for allergen activation without independently eliciting itch. This γδ T cell-IL-3 signalling axis further acts by means of STAT5 to promote neuropeptide production and the initiation of allergic immunity. These results reveal an endogenous immune rheostat that sits upstream of and governs sensory neuronal responses to allergens on first exposure. This pathway may explain individual differences in allergic susceptibility and opens new therapeutic avenues for treating allergic diseases.


Subject(s)
Hypersensitivity , Pruritus , STAT5 Transcription Factor , Sensory Receptor Cells , Signal Transduction , Animals , Mice , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/immunology , Pruritus/immunology , Pruritus/metabolism , STAT5 Transcription Factor/metabolism , Hypersensitivity/immunology , Signal Transduction/immunology , Male , Female , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, Antigen, T-Cell, gamma-delta/immunology , Allergens/immunology , Janus Kinase 2/metabolism , Humans , Mice, Inbred C57BL , Epidermis/innervation , Epidermis/immunology , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism
2.
Immunol Rev ; 326(1): 83-101, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39092839

ABSTRACT

Food allergy is classically characterized by an inappropriate type-2 immune response to allergenic food antigens. However, how allergens are detected and how that detection leads to the initiation of allergic immunity is poorly understood. In addition to the gastrointestinal tract, the barrier epithelium of the skin may also act as a site of food allergen sensitization. These barrier epithelia are densely innervated by sensory neurons, which respond to diverse physical environmental stimuli. Recent findings suggest that sensory neurons can directly detect a broad array of immunogens, including allergens, triggering sensory responses and the release of neuropeptides that influence immune cell function. Reciprocally, immune mediators modulate the activation or responsiveness of sensory neurons, forming neuroimmune feedback loops that may impact allergic immune responses. By utilizing cutaneous allergen exposure as a model, this review explores the pivotal role of sensory neurons in allergen detection and their dynamic bidirectional communication with the immune system, which ultimately orchestrates the type-2 immune response. Furthermore, it sheds light on how peripheral signals are integrated within the central nervous system to coordinate hallmark features of allergic reactions. Drawing from this emerging evidence, we propose that atopy arises from a dysregulated neuroimmune circuit.


Subject(s)
Allergens , Food Hypersensitivity , Neuroimmunomodulation , Sensory Receptor Cells , Humans , Food Hypersensitivity/immunology , Animals , Sensory Receptor Cells/immunology , Sensory Receptor Cells/metabolism , Allergens/immunology , Skin/immunology
3.
bioRxiv ; 2023 Apr 28.
Article in English | MEDLINE | ID: mdl-37163060

ABSTRACT

Group 2 innate lymphoid cells (ILC2s) cooperate with adaptive Th2 cells as key organizers of tissue type 2 immune responses, while a spectrum of innate and adaptive lymphocytes coordinate early type 3/17 immunity. Both type 2 and type 3/17 lymphocyte associated cytokines are linked to tissue fibrosis, but how their dynamic and spatial topographies may direct beneficial or pathologic organ remodelling is unclear. Here we used volumetric imaging in models of liver fibrosis, finding accumulation of periportal and fibrotic tract IL-5 + lymphocytes, predominantly ILC2s, in close proximity to expanded type 3/17 lymphocytes and IL-33 high niche fibroblasts. Ablation of IL-5 + lymphocytes worsened carbon tetrachloride-and bile duct ligation-induced liver fibrosis with increased niche IL-17A + type 3/17 lymphocytes, predominantly γδ T cells. In contrast, concurrent ablation of IL-5 + and IL-17A + lymphocytes reduced this progressive liver fibrosis, suggesting a cross-regulation of type 2 and type 3 lymphocytes at specialized fibroblast niches that tunes hepatic fibrosis.

4.
Immunity ; 55(2): 254-271.e7, 2022 02 08.
Article in English | MEDLINE | ID: mdl-35139352

ABSTRACT

Allergic immunity is orchestrated by group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells prominently arrayed at epithelial- and microbial-rich barriers. However, ILC2s and Th2 cells are also present in fibroblast-rich niches within the adventitial layer of larger vessels and similar boundary structures in sterile deep tissues, and it remains unclear whether they undergo dynamic repositioning during immune perturbations. Here, we used thick-section quantitative imaging to show that allergic inflammation drives invasion of lung and liver non-adventitial parenchyma by ILC2s and Th2 cells. However, during concurrent type 1 and type 2 mixed inflammation, IFNγ from broadly distributed type 1 lymphocytes directly blocked both ILC2 parenchymal trafficking and subsequent cell survival. ILC2 and Th2 cell confinement to adventitia limited mortality by the type 1 pathogen Listeria monocytogenes. Our results suggest that the topography of tissue lymphocyte subsets is tightly regulated to promote appropriately timed and balanced immunity.


Subject(s)
Inflammation/immunology , Interferon-gamma/immunology , Lymphocyte Subsets/immunology , Th2 Cells/immunology , Animals , Cell Death/immunology , Cell Movement/immunology , Hypersensitivity/immunology , Immunity, Innate , Interleukin-33/immunology , Interleukin-5/metabolism , Listeria monocytogenes , Listeriosis/immunology , Listeriosis/mortality , Liver/immunology , Lung/immunology , Lymphocyte Subsets/metabolism , Lysophospholipids/immunology , Mice , Parenchymal Tissue/immunology , Sphingosine/analogs & derivatives , Sphingosine/immunology , Th1 Cells/immunology , Th2 Cells/metabolism
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