Neuropilin-1 mediates lung tissue-specific control of ILC2s function in type 2 immunity
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PROVIDER: PRJNA714077 | ENA |
REPOSITORIES: ENA
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Project description:ILC2s are highly heterogeneous tissue-resident lymphocytes that regulate inflammation and tissue homeostasis in health and disease. But how they integrate to the respective tissue microenvironment to perform tissue-supportive functions remain poorly defined. Here, we identify neuropilin-1, which is induced postnatally and sustained by lung-derived TGFβ1, as a tissue signature of lung ILC2s. Genetic ablation or pharmacological inhibition of Nrp1 suppresses ILC2s function and protects mice from the development of pulmonary fibrosis. Mechanistically, TGFβ1-Nrp1 signaling enhances ILC2s function and type 2 immunity through upregulation of IL-33 receptor ST2 expression. Our findings identify Nrp1 as a tissue-specific regulator of lung-resident ILC2s activation and highlight Nrp1 as a potential therapeutic target for pulmonary fibrosis
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Project description:Group 2 innate lymphoid cells (ILC2s) in the lung are stimulated by inhaled allergens. ILC2s do not directly recognize allergens but they are stimulated by cytokines including interleukin (IL)-33 released by damaged epithelium.Lung ILC2s, upon stimulation, produce T helper 2 cell-type cytokines inducing T cell independent allergic lung inflammation. We now report that lung ILC2s, upon activation by an allergen or IL-33, acquire the properties of memory cells. The activated ILC2s initially proliferate and secrete cytokines, followed by a contraction phase as they stop producing cytokines. Nevertheless, some persist long after the resolution of the inflammation and acquire intrinsic capacities to react to unrelated allergens more vigorously than naïve ILC2s, thus mediating a severe allergic lung inflammation. Gene expression profiles of the previously activated ILC2s show a gene signature of memory T cells. These antigen non-specific memory ILC2s may explain why asthma patients are often sensitized to multiple allergens. ILC2s were isolated from mouse lungs from naive and IL-33 injected mice 4 days, 14 days and 4 months after the initial treatment. RNA was extracted from those ILC2 populations and analyzed for gene expression profiles. RNA was also extracted from ILC2s isolated from lung draining mediastinal lymph node (mLN) 4 days and 14 days after IL-33 treatment.
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Project description:Group 2 Innate Lymphoid Cells (ILC2s) are key players in type 2 immunity and contribute to maintaining homeostasis and responding to inflammation. ILC2s are implicated in the development of type 2 inflammation-mediated chronic disorders like asthma. While memory ILC2s have been identified in mouse, it is unknown whether human ILC2s can acquire immunological memory. Here, we demonstrate the persistence of CD45RO, a marker previously linked to inflammatory ILC2s, in resting ILC2s that have undergone prior activation. A high proportion of these cells concurrently reduce the expression of the canonical ILC marker CD127 in a tissue specific manner. Through isolation and in vitro stimulation of CD127- CD45RO+ ILC2s, we observed an augmented ability to proliferate and produce cytokines. CD127- CD45RO+ ILC2s are found in both healthy and inflamed tissues and display a gene signature of cell activation. Our findings suggest that human ILC2s can acquire innate immune memory and warrants a revision of the current strategies to identify human ILC2s.
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Project description:Regulatory T cells (Tregs), lymphocytes that suppress immunological reactions, are of great interest for our comprehension of homeostasis and regulation in the immune system and as a therapeutic target in the treatment of both immune-mediated pathologies and reactivation of the immune response in patients with cancer. Understanding the molecular mechanisms by which these cells are regulated in respone to their environment will help to inform clinical strategies targeting Tregs. We hypothesised that Neuropilin-1, a transmembrane co-receptor for ligands of the semaphorin and growth factor families, promotes the suppressive function of human Tregs. Utilising in vitro lentivirus-mediated transduction with shRNA to knock down neuropilin-1 in primary human Tregs, we demonstrated that neuropilin-1 knockdown Tregs were severely impaired in their capacity to suppress cell proliferation in vitro and in their ability to prolong allograft survival in a humanised mouse model of transplantation. While neuropilin-1-KD Tregs exhibited no defects in survival, proliferation and activation upon stimulation in vitro, we hypothesised that loss of NRP1 expression would alter the global gene expression profile of human Tregs, revealing a NRP1-dependent Treg-associated transcriptional signature.
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Project description:This experiment sought to determine whether estrogen could directly activate changes in gene transcription in lung and uterine ILC2s, whether such changes differed between lung and uterine ILC2s, and compared baseline gene expression between ILC2s from those organs. ILC2s, defined as lineage (CD3e, CD14, CD16/32 and B220) negative, CD25 positive and CD44 high lymphocytes, were sorted by flow cytometry from 8-12 week old BALB/c mice and cultured overnight in RPMI 1640 with 10% charcoal/dextran treated calf serum in the absence or presence of 100 ng/ml estrogen. RNA was extracted from the cells after culture.
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Project description:Group 2 innate lymphoid cells (ILC2s) reside in multiple tissues including lymphoid organs and barrier surfaces, and secrete type 2 cytokines including interleukin (IL)-5, IL-9 and IL-13. These cells participate in multiple physiological processes including allergic inflammation, tissue repair, metabolic homeostasis and host defense against helminth infections. Recent studies indicate that neuropeptides can play an important role in regulating ILC2 responses, however, the mechanisms that underlie these processes in vivo remain incompletely defined. Here, we identify that activated ILC2s upregulate choline acetyltransferase (ChAT)—the enzyme responsible for the biosynthesis of acetylcholine (ACh)—following infection with the helminth parasite Nippostrongylus brasiliensis or treatment with alarmins or cytokines including IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). ILC2s also express acetylcholine receptors (AChRs), and ACh administration promotes ILC2 cytokine production and elicits expulsion of helminth infection. In accordance with this, ChAT deficiency in ILC2s leads to defective ILC2 responses and impaired immunity against helminth infection. Together, these results reveal a previously unrecognized role of the ChAT-ACh pathway in promoting type 2 innate immunity to helminth infection.
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Project description:To investigate the function of Neuropilin-1 (NRP-1) in Foxp3+ regulatory T (Treg) cell stability and function, we cultured naïve CD4+ T cells under induced Treg cell (iTreg)-differentiating condition. We then flow sorted NRP-1+ and NRP-1- iTreg cells and performed gene expression profiling analysis.
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Project description:We analyzed the total proteome of group 2 innate lymphoid cells (ILC2s) after different stimulation with interleukin-33 (IL-33), a cytokine playing a critical role in human asthma, and TL1A, a TNF-family cytokine also known to activate ILC2s. Upon combined stimulation with IL-33 plus TL1A, we show that lung ILC2s produce high amounts of IL-9 and acquire a transient ‘ILC9’ phenotype. This phenotype is characterized by simultaneous production of large amounts of type 2 cytokines (IL-5, IL-13 and IL-9), induction of the IL-2 receptor CD25 (Il2ra), and of the transcription factors IRF4, JunB and BATF, that form immune-specific complexes known to induce IL-9 expression.
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Project description:We found that CD45, a membrane bound tyrosine phosphatase important for T cell development, negatively regulated ILC2s in a cell-intrinsic manner. ILC2s in CD45-deficient mice exhibited enhanced proliferation and maturation in bone marrow and hyperactivated phenotypes in lung with alteration of cell metabolism.
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