FOXO1 pathway activation by VISTA immune checkpoint restrains pulmonary ILC2 functions
Mohammad Hossein Kazemi, … , Kei Sakano, Omid Akbari
Mohammad Hossein Kazemi, … , Kei Sakano, Omid Akbari
Published January 2, 2025
Citation Information: J Clin Invest. 2025;135(4):e184932. https://doi.org/10.1172/JCI184932.
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Research Article Immunology Inflammation

FOXO1 pathway activation by VISTA immune checkpoint restrains pulmonary ILC2 functions

Abstract

Group 2 innate lymphoid cells (ILC2s) play a pivotal role in the development of airway hyperreactivity (AHR). However, the regulatory mechanisms governing ILC2 function remain inadequately explored. This study uncovers V-domain Ig suppressor of T cell activation (VISTA) as an inhibitory immune checkpoint crucial for modulating ILC2-driven lung inflammation. VISTA is upregulated in activated pulmonary ILC2s and plays a key role in regulating lung inflammation, as VISTA-deficient ILC2s demonstrate increased proliferation and function, resulting in elevated type 2 cytokine production and exacerbation of AHR. Mechanistically, VISTA stimulation activates Forkhead box O1 (FOXO1), leading to modulation of ILC2 proliferation and function. The suppressive effects of FOXO1 on ILC2 effector function were confirmed using FOXO1 inhibitors and activators. Moreover, VISTA-deficient ILC2s exhibit enhanced fatty acid oxidation and oxidative phosphorylation to meet their high energy demands. Therapeutically, VISTA agonist treatment reduces ILC2 function both ex vivo and in vivo, significantly alleviating ILC2-driven AHR. Our murine findings were validated in human ILC2s, whose function was reduced ex vivo by a VISTA agonist, and in a humanized mouse model of ILC2-driven AHR. Our studies unravel VISTA as an immune checkpoint for ILC2 regulation via the FOXO1 pathway, presenting potential therapeutic strategies for allergic asthma by modulating ILC2 responses.

Authors

Mohammad Hossein Kazemi, Zahra Momeni-Varposhti, Xin Li, Benjamin P. Hurrell, Yoshihiro Sakano, Stephen Shen, Pedram Shafiei-Jahani, Kei Sakano, Omid Akbari

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Figure 9

VISTA regulates human ILC2 function and alleviates ILC2-driven AHR in humanized mice.

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VISTA regulates human ILC2 function and alleviates ILC2-driven AHR in hu...
(A–F) Human peripheral ILC2s (hILC2s) were stimulated with or without rhIL-33 (100 ng/mL). (B) Representative plots of VISTA expression levels and corresponding quantification (as MFI). (C–F) hILC2s were treated with 5 μg/mL rhVSIG3 and vehicle control. (C and D) Representative plots of GATA-3 (C) and Ki67 (D) expression levels and corresponding quantification (as MFI). (E) Cytokine levels in hILC2 supernatant (per 103 ILC2s). (F) Representative plots of FOXO1 expression levels and corresponding quantification (as MFI) following 1 hour treatment with rhVSIG3. (G–J) A total of 2 × 105 hILC2s were transferred intravenously into Rag2–/–GC–/– mice, followed by intranasal challenge with rhIL-33. On days 1 and 3, mice intravenously received 2 mg/kg rhVSIG3 or vehicle. (H) Lung resistance in response to elevating doses of methacholine. (I) Total number of ILC2s per lung. (J) Total number of eosinophils in BAL fluid. Data are presented as mean + SEM and are representative of at least 2 independent experiments. Statistical significance was assessed using either 2-tailed Student’s t test (B–F, I, and J) or 1-way ANOVA followed by Tukey’s post hoc test (H); *P < 0.05, **P < 0.01.