Remember me
Research ArticleImmunologyPulmonology
Open Access | 
10.1172/JCI177242
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by
Chowdhury, N.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Cephus, J. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Henriquez Pilier, E. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Wolf, M. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Madden, M. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Kuehnle, S. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by McKernan, K. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Jennings, E. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by
Arner, E.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Heintzman, D. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Chi, C. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Sugiura, A. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Stier, M. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Voss, K. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by
Ye, X.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Scales, K. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Krystofiak, E. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by
Gandhi, V.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Guzy, R. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Cahill, K. in: JCI | PubMed | Google Scholar
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by
Sperling, A.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by
Peebles, R.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by
Rathmell, J.
in:
JCI
|
PubMed
|
Google Scholar
|
1Department of Pathology, Microbiology, and Immunology,
2Vanderbilt Center for Immunobiology, and
3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
5Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
6Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Dawn C. Newcomb, T-2220 Medical Center North, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: 615.875.7782; Email: dawn.newcomb@vumc.org.
Find articles by Newcomb, D. in: JCI | PubMed | Google Scholar
Published October 15, 2024 - More info
Published in Volume 134, Issue 23 on December 2, 2024
Related article:
Abstract
Sex-based differences in autoimmune disease susceptibility have long been recognized, prompting investigations into how sex hormones influence immunity. Recent advances suggest that hormones may shape immune responses by altering cellular metabolism. In this issue of the JCI, Chowdhury et al. authenticates this model, showing that androgen receptor signaling modulates T helper 17 (Th17) cell metabolism, specifically glutaminolysis, reducing airway inflammation in males. This work provides insight into sex-specific regulation of immunity, highlighting the interplay between hormones, metabolism, and immune function. The findings raise intriguing questions about how hormonal fluctuations affect immunity and how sex-specific metabolic pathways might be leveraged for targeted therapies in autoimmune diseases.
Authors
Nikita L. Mani, Samuel E. Weinberg
× AbstractFemale 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+ 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 sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.
Graphical Abstract
Introduction
Cellular metabolism drives CD4+ T cell differentiation and stability, and CD4+ T cell metabolic pathways are promising therapeutic targets for cancers, autoimmune diseases, and asthma (1–3). Once activated, effector CD4+ T cells substantially increase glycolysis to proliferate and undergo clonal expansion (2, 4). However, the reliance on other metabolic pathways is required for maximal effector function and varies between the CD4+ T cell subsets of Th1, Th2, Th17, and regulatory T cells (Tregs) (3–6). Prior research focused on the metabolic pathways required for Th1, Th17, and Tregs, as these CD4+ T cell subsets are critical in pathogenesis of cancers and autoimmune diseases. Here, we focus on how androgen signaling through the androgen receptor (AR) alter metabolic pathways critical for Th17 and Th2 cells, cell types important in allergic airway inflammation and asthma.
Differential and overlapping metabolic pathways are essential for Th2 and Th17 cells. Th2 cells rely upon fatty acid oxidation and PPAR-γ signaling (7), and we recently showed that glutaminolysis was important for Th2 function during allergic airway inflammation (8). Th17 cells require de novo fatty acid synthesis (9) and one carbon metabolism (10) for differentiation, effector function, and cytokine expression (11). Further, glutaminolysis is essential for Th17 cell differentiation and effector function, and glutaminolysis may also inhibit Th1 cell differentiation (8, 11–13). Glutaminolysis involves the uptake and conversion of glutamine to glutamate by glutaminase (GLS). Glutamate can then be converted to α-ketoglutarate, which can enter the tricarboxylic acid (TCA) cycle, be converted to glutathione (GSH) for ROS management, modify chromatin methylation patterns, and/or be used for other metabolic processes (1, 14–16).
While metabolic needs for Th1, Th2, and Th17-mediated diseases have been examined, it remains unexplored how sex hormones modify these metabolic pathways. Understanding the role of sex hormones is critical since there is a female predominance in the prevalence and/or severity of many immune-mediated diseases, including asthma, multiple sclerosis, lupus, rheumatoid arthritis, and type I diabetes (17). This female sex bias has been attributed to a myriad of reasons, including the impact of sex hormones, X and Y chromosomal differences, and social and environmental factors (17, 18). Yet, the role of immunometabolism is unclear.
Prior research on sex hormone signaling and cell metabolism in cancer showed androgens signaling through the AR altered cell metabolism. In prostate cancer cells, AR signaling dysregulated glycolysis, the TCA cycle, amino acid metabolism, and fatty acid metabolism through transcriptional, epigenetic, and amino acid transport changes (19–21). Further, AR signaling increased glutamine metabolism and utilization in gliomas (22). However, cancer cells can have dysregulation of normal metabolic patterns and dysregulation of sex hormone receptor expression, and the impact of AR signaling on CD4+ T cell metabolism during inflammation is unknown. Various studies described the impact of AR signaling on immune cells and T cells through reductions in function or increased expression of exhaustion markers (23–26), but defining how sex hormones affect CD4+ T cell metabolism would provide a foundational mechanism for sex differences in CD4+ T cell subset effector function.
A previous study from our group showed that patients with asthma had increased numbers of CD4+ effector T cells and increased expression of metabolic enzymes in their CD4+ T cells compared with those of people in the healthy control group (8). However, the sex of participants and the effect of sex hormones on these cells was not considered. Given the importance of distinct metabolic programs on T cell function, we sought to determine the role of AR signaling in modifying CD4+ T helper cell metabolism in vitro using human and mouse cells and in vivo using a mouse model of allergen-induced airway inflammation. Here, we show that AR signaling directly decreased glutamine uptake and glutaminolysis in Th17 cells to reduce IL-17A–mediated inflammation.
ResultsMetabolic markers in human CD4+ T cells from the mediastinal lymph nodes are decreased in men compared with women. Metabolic markers are differentially expressed based on the metabolic requirements of CD4+ T cells (8, 13, 27). Using excised mediastinal lymph nodes from deceased human male and female donors (ages 18–55) that did not qualify for lung transplant, we conducted mass cytometry (CyTOF) using an antibody panel focused on T cells and metabolic markers (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI177242DS1). Donors chosen were matched for age, race, and ethnicity (Supplemental Table 2). Surface expression of chemokine receptors, CCR4, and CXCR3, as well as other surface markers were used to identify CD4+ T cells and subset these cells into Th1, Th2, Treg, and Th17 cells as previously described in PBMCs and lung-draining lymph nodes (Figure 1A) (28, 29). Gating strategies and CD4+ T cell population definitions are shown in Supplemental Figure 1. The median expression of metabolic markers was also determined in CD4+ T cell subsets (Figures 1, B–D and Supplemental Figure 2). Metabolic markers included Glut1 for glycolysis, GLUD1 for glutaminolysis, Cpt1a for fatty acid metabolism, and Grim19, ATP5a, and cytochrome C as various parts of the electron transport chain in mitochondrial metabolism. The CD4+ T cells and all subsets of Th1, Th2, Th17, and Tregs had decreased expression in GLUD1 in male compared with female individuals (Figure 1B). Additionally, Grim19 was decreased in CD4+ T cells, Th17, and Tregs in males compared with females, and ATP5a was decreased in Tregs from male compared with female individuals (Figures 1D and Supplemental Figure 2B). Other metabolic markers, Glut1, Cpt1a, and cytochrome C, were not different between the male and female CD4+ T cell subsets that were examined (Figures 1C and Supplemental Figure 2, A and C). These data show that effector CD4+ T cells from human lung draining lymph nodes from males are metabolically distinct from T cells from females, with decreased expression of GLUD1 and Grim19.
Figure 1CyTOF of lung-draining lymph nodes of deceased donor patients reveals sex differences in T cells and metabolic protein expression. CyTOF was conducted on human lung draining lymph nodes from deidentified female and male deceased donors. (A) UMAP visualization of cell surface markers in all samples. (B–D) Median expression of metabolic markers on CD4+ T cells, Th1, Th2, Th17, and Treg cells. Gating strategies and population definitions are shown in Figure S1. Data are expressed as mean ± SEM: n = 14 females and n = 17 males *P < 0.05, **P < 0.01; 2-tailed Mann-Whitney U test. See Supplemental Figures 1 and 2 and Supplemental Tables 1 and 2.
AR signaling intrinsically decreases Th17- but not Th2-mediated inflammation. Reports from our group and others showed that glutaminolysis increased airway inflammation and IL-17A production from Th17 cells (8) and that AR signaling decreased type 2 and nontype 2 inflammation during allergic airway inflammation (25, 26, 30). Specifically, we previously showed a cell-intrinsic role of AR signaling in Th17 cell–driven inflammation in a house dust mite (HDM) model through bone marrow chimera experiments using T cells from WT male and ArTfm male mice (25). Based on these findings, we next determined if AR signaling in CD4+ T cells attenuated HDM-induced airway inflammation and modified expression of metabolites in CD4+ T cells. As shown in Figure 2A, Arfl/fl female, Cd4Cre+ Arfl/fl female, Arfl/0 male, and Cd4Cre+ Arfl/0 male mice were challenged with 40 μg of HDM 3 times a week for 3 weeks. Lungs and bronchoalveolar lavage (BAL) fluid were harvested 1 day after the last challenge to assess airway inflammation. HDM-challenged Arfl/fl female mice had increased numbers of eosinophils and neutrophils in the BAL fluid compared with Arfl/0 male mice, and Cd4Cre+ Arfl/0 male mice had increased neutrophil infiltration and no difference in eosinophils compared with Arfl/0 male mice (Figure 2B). IL-13 and IL-17 cytokine levels in BAL fluid were also significantly increased in Arfl/fl female mice compared Arfl/0 male mice, and Cd4Cre+ Arfl/0 male mice had increased IL-13 and IL-17 levels compared with Arfl/0 male mice (Figure 2C). To determine if AR signaling in CD4+ T cells attenuated allergen-induced airway hyperresponsiveness (AHR) to methacholine, a physiological hallmark of asthma, we measured airway resistance in response to increasing concentrations of nebulized methacholine via Flexivent. Similar to what we have previously reported (25, 26), Arfl/fl female mice had increased AHR compared with Arfl/0 male mice (Figure 2D, solid red versus solid blue lines). Cd4Cre+ Arfl/0 male mice had similar AHR compared with Arfl/fl female mice (dotted blue line overlaid with solid red line) and no significant difference was determined between Cd4Cre+ Arfl/fl female and Arfl/fl female mice (dotted and solid red lines). These data show that AR signaling in CD4+ T cells attenuate HDM-induced airway inflammation and AHR.
Figure 2AR signaling in CD4+ T cells reduces Th17-driven neutrophilic inflammation during airway inflammation. (A) Model of HDM allergen challenge. Female and male Arfl and Cd4Cre+ Ar fl mice were challenged intranasally with 40 μg of HDM 3 times per week for 3 weeks. BAL fluid and lungs were harvested 24 hours after the last challenge. (B) Quantification of eosinophils and neutrophils in the BAL fluid from mice after HDM challenge. (C) IL-13 and IL-17A protein expression in BAL fluid after HDM challenge. (D) Airway hyperresponsiveness as measured by FlexiVent with increasing doses of methacholine was also conducted on HDM-challenged female and male Arfl and Cd4Cre+Arfl mice 48 hours after last challenge (Data show mean ± SEM, n = 4–6 mice per group). (E) Representative flow diagrams of IL-13+ Th2 cells and IL-17A+ Th17 cells. (F) Quantification of lung Th2 and Th17 cells after HDM challenge (G and H) Expression of GLUD1, Glut1, HIF1-α, and pS6 in lung Th2 cells (G) and Th17 cells (H) after HDM challenge. (B, C, and E–H) Data are expressed as mean ± SEM: n = 7–9 mice per group combined from 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; ANOVA with Tukey’s post hoc test. See Supplemental Figu
Comments (0)