VISTA regulates lung ILC2 metabolism and effector function through FOXO1 2223

Abstract Description Growing evidence highlights the pivotal role of group 2 innate lymphoid cells (ILC2s) in the development of airway hyperreactivity (AHR), requiring further exploration of the inhibitory mechanisms regulating ILC2 activity. This research identifies V-domain Ig suppressor of T cell activation (VISTA) as an inhibitory immune checkpoint that controls ILC2-driven lung inflammation. VISTA is upregulated in activated lung ILC2s and is crucial for modulating lung inflammation, as ILC2s lacking VISTA show increased activity, leading to elevated type-2 cytokine production and worsened AHR. VISTA stimulation reduces AKT phosphorylation, activates Forkhead box O1 (FOXO1) and modulates NF-kB signaling, leading to ILC2 suppression. Using FOXO1 inhibitors and activators, we further confirm the suppressive effects of FOXO1 on ILC2 effector function. Metabolically, ILC2s lacking VISTA manifest increased fatty acid oxidation and oxidative phosphorylation to meet higher energy demands. Therapeutically, treatment with VISTA agonist antibody or recombinant ligand reduces ILC2 function in both ex vivo and in vivo settings, alleviating ILC2-driven AHR. Furthermore, VISTA is upregulated in activated human ILC2s and treatment with VISTA agonist suppresses human ILC2 function ex vivo and in a humanized AHR mouse model. These findings position VISTA as a novel immune checkpoint for regulating ILC2s, offering promising therapeutic avenues for allergic asthma by modulating ILC2 responses. Funding Sources This study was financially supported by National Institutes of Health Public Health Service grants R01 HL144790, R01 HL151493, R01 AI145813, R01 AI169687, R01 HL151769, and R01 HL159804 (O. Akbari). Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)