The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of interleukin-10-producing type 2 innate lymphoid cells (IL-10+ ILC2s) in modulating grass-pollen allergy. We demonstrate that KLRG1+ but not KLRG1– ILC2 produced IL-10 upon activation with IL-33 and retinoic acid. These cells attenuated Th responses and maintained epithelial cell integrity. IL-10+ KLRG1+ ILC2s were lower in patients with grass-pollen allergy when compared to healthy subjects. In a prospective, double-blind, placebo-controlled trial, we demonstrated that the competence of ILC2 to produce IL-10 was restored in patients who received grass-pollen sublingual immunotherapy. The underpinning mechanisms were associated with the modification of retinol metabolic pathway, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathways in the ILCs. Altogether, our findings underscore the contribution of IL-10+ ILC2s in the disease-modifying effect by allergen immunotherapy.
Bibliografisk noteFunding Information:
We would like to acknowledge Jane Srivastava and Radhika Patel for help with cell sorting, Susanne Reinartz for help with experimental design, Danielle van Egmond, Esther de Groot, and Maryse Tempert for samples acquisition and experimental work, and colleagues from flow cytometry core facility Amsterdam UMC for help with flow cytometry. The Imperial BRC Genomics Facility provided resources and support that contributed to results reported within this paper. This study was supported by the Imperial College Trust and the NIHR Imperial Biomedical Research Centre . H.S. was supported by an advanced grant of the ERC , # 341038 . F.Q.H, O.H., M.O., and G.M. were supported by Luxembourg National Research Fund (FNR) grants AFR-RIKEN/11228353/TregBAR (F.Q.H. and M.O.), PRIDE/11012546/NEXTIMMUNE (G.M., F.Q.H., and M.O.), and PRIDE/10907093/CRITICS (F.Q.H.).
K.G., J.A.L., U.S., M.M.L., R.C.Y.L., S.M.B., B.A.H., G.V.-N., O.H., G.M., F.Q.H., O.F., M.L.A., S.J.H.V., A.-H.M.v.d.Z., C.M.v.D., and W.F. report no conflicts of interest. E.H.S.-K. has received travel grants from ALK-Abello. Stephen Durham has received lecture fees and research funds from ALK, Denmark, manufacturer of grass allergen tablets used for sublingual immunotherapy. M.O. is a consultant for Hycor Biomedical and a co-founder of Tolerogenics SARL. Unrelated intellectual property of M.O. and the Luxembourg Institute of Health has been licensed to Tolerogenics. H.S. is a consultant for GSK for which he receives an honorarium. M.H.S. reports research grants from Immune Tolerance Network, Medical Research Council, Allergy Therapeutics, and LETI Laboratorios and lecture fees from Allergy Therapeutics and ALK.
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