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Introduction Cellular metabolism drives [CD4.sup.+] T cell differentiation and stability, and [CD4.sup.+] T cell metabolic pathways are promising therapeutic targets for cancers, autoimmune diseases, and asthma (1-3). Once activated, effector [...], Female individuals have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared with female individuals, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined that females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and that AR signaling attenuated glutamine uptake in [CD4.sup.+] T cells by reducing expression of glutamine transporters. In patients with asthma, circulating Th17 cells from men had minimal reliance upon glutamine uptake compared to Th17 cells from women. AR signaling thus attenuates glutaminolysis, demonstrating sexspecific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.

Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions. Editor's summary: Heat is one of the hallmarks of inflammation, but its effect on immune cells is not well understood. Heintzman et al. report that temperatures associated with moderate-grade fevers (39°C) both enhance the metabolism, proliferation, and effector function of mouse CD4 T cells and dampen regulatory T cell suppressive potential. In addition, febrile temperatures disrupt electron transport chain complex 1, which selectively drives apoptosis and elimination of a substantial number of mouse and human T helper 1 (TH1) cells. Those TH1 cells that can adapt by increasing their mitochondrial mass and DNA damage responses, however, exhibit genomic integrity and augmented effector functions. —Seth Thomas Scanlon [ABSTRACT FROM AUTHOR]

Introduction A sex bias exists in many autoimmune diseases and chronic inflammatory disorders, including asthma. Before puberty, males have increased asthma prevalence compared with females. After puberty, females have increased [...], 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.sup.+] Tregs suppress and [ST2.sup.+] 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.sup.+] Tregs and limiting the number of [ST2.sup.+] ex-Tregs and IL-[13.sup.+] Th2 cells and ex-Tregs. AR signaling also decreased Alt Ext-induced [ST2.sup.+] 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 5[alpha]-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.

Introduction Tregs are important components of the adaptive immune system that promote tolerance, prevent the development of autoimmune diseases, and suppress inflammation (1, 2). Tregs are characterized by their expression [...], 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 ([PGI.sub.2]) promoted immune tolerance in models of allergic inflammation; however, the effect of [PGI.sub.2] on Treg function was not investigated. Tregs from mice deficient in the [PGI.sub.2] receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared with mice in which [PGI.sub.2] 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 [PGI.sub.2] signaling prevents Treg reprogramming toward a pathogenic phenotype. [PGI.sub.2] analogs promoted the differentiation of naive T cells to Tregs in both mice and humans via repression of [beta]-catenin signaling. Finally, a missense variant in IP in humans was strongly associated with chronic obstructive asthma. Together, these data support that [PGI.sub.2] signaling licenses Treg suppressive function and that [PGI.sub.2] is a therapeutic target for enhancing Treg function.