Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction

Abstract

Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue-or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E 2 (PGE 2 ) into the metabolite 15-keto PGE 2 , was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-g (PPARg)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE 2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue-and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis. (C) Time course of relative HPGD mRNA expression in human Treg and Tconv cells in the presence of IL-2. (D) Immunoblotting for HPGD (top) and b-actin (bottom) in human Treg and Tconv cells after isolation (0 h) or cultivated for 48 or 72 h without stimulation (unstim) or stimulated with IL-2 (left) and densitometric analysis (right). (E and F) Relative HPGD mRNA expression in unstimulated or IL-2-stimulated human Treg cells cultured for 24 h in the presence of DMSO (control) or increasing doses of a STAT5 inhibitor (E) or JAK3 inhibitor (F). (G) ChIP qPCR analysis of human IL-2-stimulated Treg and Tconv cells with a STAT5-specific antibody. Relative enrichment of STAT5 ChIP over input normalized to immunoglobulin G (IgG) is shown. (H and I) IL-2-and STAT5-dependent activation of luciferase reporter constructs. (H) IL-2-induced HPGD promoter activity. (I) STAT5-dependent HPGD induction. (J) ChIP qPCR analysis of human expanded cord blood Treg cells with a FOXP3-specific antibody. Relative enrichment of FOXP3 ChIP over input normalized to IgG was calculated. A region within intron 4 was used as a negative control. (K) Luciferase assay of FOXP3 binding to the respective BRs at the HPGD locus. Numbers indicate Foxp3-binding motifs within each region. (L) Relative HPGD mRNA expression in human Treg cells after silencing of FOXP3. Treg cells were transfected and cultivated for 48 h without stimulation. (A, B, G, J, and L) *p < 0.05 (paired Student's t test); (C) *p < 0.05 (two-way ANOVA with false-discovery rate [FDR]); (D-F) *p < 0.05 (one-way ANOVA with FDR); (H) *p < 0.05 (Mann-Whitney U test); (I and K) *p < 0.05 (unpaired Student's t test). Data are representative of fourteen experiments (A; mean and SEM), six experiments (B; mean and SEM), two to five experiments (L; mean and SEM), four experiments (C-F; mean and SEM), three experiments (G and J; mean and SEM), each with ...

Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells

“…Our findings are further supported by a recent study demonstrating that PGE2 exacerbates TNF-induced inflammatory responses in human intestinal epithelial cells from patients with IBD who are resistant to TNF inhibitor therapy 46 . Moreover, recent studies including ourselves have suggested that lack of PGE2-EP4 signaling in T cells reduced both chemical-triggered acute and naïve T cell transfer-induced chronic intestinal inflammation, associated with reduction of inflammatory Th1 and/or Th17 cell responses 29,47,48 . This work thus advances our understanding that PGE2 mediates intestinal inflammation through modulating the network of the gut microbiota and the host immune system involving both innate MNPs and adaptive T cell responses.…”

Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

“…In addition, a recent report has found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD) is highly expressed in VAT-Treg cells, which is dependent on PPARγ. HPGD catabolizes prostaglandin E 2 (PGE 2 ) into the metabolite 15-keto PGE 2 to suppress conventional T cell activation and proliferation (158). These results together demonstrate that Treg cells adapt to unique VAT environments for their homeostasis and function.…”

Transcriptomic profiling of human effector and regulatory T cell subsets identifies predictive population signatures

“…Treg1 cells also most highly expressed the co-inhibitory receptors LAG3 and HAVCR2 (TIM-3), and the cytolytic effectors GZMA and GZMK. By contrast, expression the TGF-β-activating molecule LRRC32 (GARP) was highest in Treg 2 cells, the decoy IL-1 receptor IL1R2 was most highly expressed by Treg 17 and Treg1/17 cells, and HPGD, which is used by Treg cells to degrade the pro-inflammatory prostaglandin PGE2 (Schmidleithner et al, 2019), was most highly expressed in Treg22 cells. Other genes implicated in Treg function including TGFB1, ITGAV, ITGB8, IL12A (a component of the antiinflammatory cytokine IL-35), CTLA4, PDCD1 (PD1), TIGIT, PRF1, and ENTPD1 (CD39) did not show strong preferential expression in any Treg population, and NT5E (CD73) was barely detected in these ex vivo isolated Treg cells.…”