ICOS: ICOS-ligand Interaction is Essential for ILC2 Function and Survival (HYP2P.322)

Abstract Type 2 Innate lymphoid cells (ILC2s) are a newly identified subset of immune cells that play important roles in the pathogenesis of allergic asthma by producing large amounts of IL-5 and IL-13. ILC2 lack lineage markers but express CD45, IL-2Rα, IL-33R and IL-7Rα. All murine ILC2s and a significant portion of human ILC2s express Inducible T-cell COStimulator (ICOS) that is essential for T cell activation and function, however, the role of ICOS in ILC2s remains unknown. We investigated the role of ICOS in the function and survival of murine and human ILC2s using ICOS-/- and RAG2-/- and humanized mice in different experimental setups. We found that:1) ICOS-/- mice show lower IL-33-induced airway hyperreactivity (AHR) and eosinophilia than wild type (WT) mice. 2) Survival and the number of ILC2s is substantially lower in ICOS-/- than WT mice. 3) Blocking anti-ICOS antibody reduces survival and the number of ILC2s in WT mice. 4) Ex vivo stimulated ICOS-/- ILC2s show impaired IL-5 and IL-13 production compared to WT ILC2s. 5) Human peripheral ILC2s express ICOS and blocking ICOS:ICOS-Ligand interaction impairs their IL-5 and IL-13 production in vitro and IL-33 induced AHR and eosinophilia in humanized mice. 6) Human and murine ILC2s express ICOS-Ligand. 7) ICOS signaling modulates STAT5 pathway. Our results indicate that ICOS is required for the optimal function and survival of ILC2s and can be a novel therapeutic target in patients with ILC2-mediated asthma and lung inflammation.