Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming
Allison E. Norlander, … , Talal A. Chatila, R. Stokes Peebles Jr.
Allison E. Norlander, … , Talal A. Chatila, R. Stokes Peebles Jr.
Published February 2, 2021
Citation Information: J Clin Invest. 2021;131(7):e140690. https://doi.org/10.1172/JCI140690.
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Research Article Immunology Inflammation

Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming

Abstract

Tregs restrain both the innate and adaptive immune systems to maintain homeostasis. Allergic airway inflammation, characterized by a Th2 response that results from a breakdown of tolerance to innocuous environmental antigens, is negatively regulated by Tregs. We previously reported that prostaglandin I2 (PGI2) promoted immune tolerance in models of allergic inflammation; however, the effect of PGI2 on Treg function was not investigated. Tregs from mice deficient in the PGI2 receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared with mice in which PGI2 signaling was intact. IP KO Tregs had significantly enhanced expression of immunoglobulin-like transcript 3 (ILT3) compared with WT Tregs, which may contribute to the impairment of the IP KO Treg’s ability to suppress Th2 responses. Using fate-mapping mice, we reported that PGI2 signaling prevents Treg reprogramming toward a pathogenic phenotype. PGI2 analogs promoted the differentiation of naive T cells to Tregs in both mice and humans via repression of β-catenin signaling. Finally, a missense variant in IP in humans was strongly associated with chronic obstructive asthma. Together, these data support that PGI2 signaling licenses Treg suppressive function and that PGI2 is a therapeutic target for enhancing Treg function.

Authors

Allison E. Norlander, Melissa H. Bloodworth, Shinji Toki, Jian Zhang, Weisong Zhou, Kelli Boyd, Vasiliy V. Polosukhin, Jacqueline-Yvonne Cephus, Zachary J. Ceneviva, Vivek D. Gandhi, Nowrin U. Chowdhury, Louis-Marie Charbonnier, Lisa M. Rogers, Janey Wang, David M. Aronoff, Lisa Bastarache, Dawn C. Newcomb, Talal A. Chatila, R. Stokes Peebles Jr.

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Figure 8

PGI2 analogs promote human Treg differentiation.

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PGI2 analogs promote human Treg differentiation. Purified CD4+ T cells w...
Purified CD4+ T cells were cultured with IL-2 and TGF-β and increasing doses of cicaprost. (A) Representative flow cytometric analysis (n = 12). (B) Baseline-normalized percentage polarization to iTregs (n = 12). (C) MFI (n = 12). In a separate set of experiments, purified CD4+ T cells were cultured with IL-2, TGF-β, cicaprost, and inhibitors to different signaling pathways. (D) Purified CD4+ T cells were treated with 2 different concentrations of ICG001, a β-catenin inhibitor. Baseline-normalized percentage polarization to iTregs is plotted (n = 7, 3 independent experiments combined). (E) Purified CD4+ T cells were treated with 2 different concentrations of H89, a PKA inhibitor. Baseline-normalized percentage polarization to iTregs is plotted (n = 7, 3 independent experiments combined). (F) Purified CD4+ T cells were treated with 2 different concentrations of ESI09, an EPAC inhibitor. Baseline-normalized percentage polarization to iTregs is plotted (n = 7, 3 independent experiments combined). Data are represented as mean ± SEM. Statistical significance was determined by 1-way ANOVA or 2-way ANOVA. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.