Browsing by Author "Ceneviva, Zachary J."

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    Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation
    (American Society for Clinical Investigation, 2022) Gandhi, Vivek D.; Cephus, Jacqueline-Yvonne; Norlander, Allison E.; Chowdhury, Nowrin U.; Zhang, Jian; Ceneviva, Zachary J.; Tannous, Elie; Polosukhin, Vasiliy V.; Putz, Nathan D.; Wickersham, Nancy; Singh, Amrit; Ware, Lorraine B.; Bastarache, Julie A.; Shaver, Ciara M.; Chu, Hong Wei; Peebles, R. Stokes, Jr.; Newcomb, Dawn C.; Anatomy, Cell Biology and Physiology, School of Medicine
    Women have higher prevalence of asthma compared with men. In asthma, allergic airway inflammation is initiated by IL-33 signaling through ST2, leading to increased IL-4, IL-5, and IL-13 production and eosinophil infiltration. Foxp3+ Tregs suppress and ST2+ Tregs promote allergic airway inflammation. Clinical studies showed that the androgen dehydroepiandrosterone (DHEA) reduced asthma symptoms in patients, and mouse studies showed that androgen receptor (AR) signaling decreased allergic airway inflammation. Yet the impact of AR signaling on lung Tregs remains unclear. Using AR-deficient and Foxp3 fate-mapping mice, we determined that AR signaling increased Treg suppression during Alternaria extract (Alt Ext; allergen) challenge by stabilizing Foxp3+ Tregs and limiting the number of ST2+ ex-Tregs and IL-13+ Th2 cells and ex-Tregs. AR signaling also decreased Alt Ext–induced ST2+ Tregs in mice by limiting expression of Gata2, a transcription factor for ST2, and by decreasing Alt Ext–induced IL-33 production from murine airway epithelial cells. We confirmed our findings in human cells where 5α-dihydrotestosterone (DHT), an androgen, decreased IL-33–induced ST2 expression in lung Tregs and decreased Alt Ext–induced IL-33 secretion in human bronchial epithelial cells. Our findings showed that AR signaling stabilized Treg suppressive function, providing a mechanism for the sex difference in asthma.
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    Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming
    (American Society for Clinical Investigation, 2021) Norlander, Allison E.; Bloodworth, Melissa H.; Toki, Shinji; Zhang, Jian; Zhou, Weisong; Boyd, Kelli; Polosukhin, Vasiliy V.; Cephus, Jacqueline-Yvonne; Ceneviva, Zachary J.; Gandhi, Vivek D.; Chowdhury, Nowrin U.; Charbonnier, Louis-Marie; Rogers, Lisa M.; Wang, Janey; Aronoff, David M.; Bastarache, Lisa; Newcomb, Dawn C.; Chatila, Talal A.; Peebles, R. Stokes, Jr.; Anatomy, Cell Biology and Physiology, School of Medicine
    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.