Auteurs
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 as an immune checkpoint in different inflammatory diseases.
Objective:
Here we investigated the expression of LAIR-1 and assessed its role in human and murine ILC2s.
Methods:
WT and LAIR-1 KO 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 using knock-out 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 physiological 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.