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LAIR-1 acts as an immune checkpoint on activated ILC2s and regulates the induction of airway hyperreactivity.
- Source :
-
The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2022 Jan; Vol. 149 (1), pp. 223-236.e6. Date of Electronic Publication: 2021 Jun 16. - Publication Year :
- 2022
-
Abstract
- Background: Type 2 innate lymphoid cells (ILC2s) are relevant players in type 2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine secretion. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered to be an immune checkpoint in different inflammatory diseases.<br />Objective: Our aim here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s.<br />Methods: Wild-type and LAIR-1 knockout mice were intranasally challenged with IL-33, and pulmonary ILC2s were sorted to perform an ex vivo comparative study based on RNA sequencing and flow cytometry. We next studied the impact of LAIR-1 deficiency on AHR and lung inflammation by using knockout mice and adoptive transfer experiments in Rag2 <superscript>-/-</superscript> Il2rg <superscript>-/-</superscript> mice. Knockdown antisense strategies and humanized mice were used to assess the role of LAIR-1 in human ILC2s.<br />Results: We have demonstrated that LAIR-1 is inducible on activated ILC2s and downregulates cytokine secretion and effector function. LAIR-1 signaling in ILC2s was mediated via inhibitory pathways, including SHP1/PI3K/AKT, and LAIR-1 deficiency led to exacerbated ILC2-dependent AHR in IL-33 and Alternaria alternata models. In adoptive transfer experiments, we confirmed the LAIR-1-mediated regulation of ILC2s in vivo. Interestingly, LAIR-1 was expressed and inducible in human ILC2s, and knockdown approaches of Lair1 resulted in higher cytokine production. Finally, engagement of LAIR-1 by physiologic ligand C1q significantly reduced ILC2-dependent AHR in a humanized ILC2 murine model.<br />Conclusion: Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce allergic AHR and lung inflammation.<br /> (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adoptive Transfer
Alternaria
Alternariosis physiopathology
Animals
Cytokines immunology
Female
Humans
Immunity, Innate
Interleukin-33 pharmacology
Lung immunology
Lung physiopathology
Lymphocyte Transfusion
Male
Mice, Inbred C57BL
Mice, Knockout
Pneumonia physiopathology
Receptors, Immunologic genetics
Respiratory Hypersensitivity physiopathology
Mice
Alternariosis immunology
Lymphocytes immunology
Pneumonia immunology
Receptors, Immunologic immunology
Respiratory Hypersensitivity immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-6825
- Volume :
- 149
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of allergy and clinical immunology
- Publication Type :
- Academic Journal
- Accession number :
- 34144112
- Full Text :
- https://doi.org/10.1016/j.jaci.2021.05.042