1. Academic Validation
  2. LAIR-1 acts as an immune checkpoint on activated ILC2s and regulates the induction of airway hyperreactivity

LAIR-1 acts as an immune checkpoint on activated ILC2s and regulates the induction of airway hyperreactivity

  • J Allergy Clin Immunol. 2022 Jan;149(1):223-236.e6. doi: 10.1016/j.jaci.2021.05.042.
Doumet Georges Helou 1 Pedram Shafiei-Jahani 1 Benjamin P Hurrell 1 Jacob D Painter 1 Christine Quach 1 Emily Howard 1 Omid Akbari 2
Affiliations

Affiliations

  • 1 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
  • 2 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif. Electronic address: akbari@usc.edu.
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.

Objective: Our aim here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s.

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-/-Il2rg-/- mice. Knockdown antisense strategies and humanized mice were used to assess the role of LAIR-1 in human ILC2s.

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.

Conclusion: Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce allergic AHR and lung inflammation.

Keywords

ILC2; LAIR-1; airway hyperreactivity; allergic asthma; immune checkpoints.

Figures
Products