A.He. performed experiments and analyzed data. L.B. generated and provided critical reagents. T.S. and A.Ts assisted with mRNAseq and ATAC-seq data analysis, interpretation and T.S. generated figures. J.Z. and A.Te. performed and analyzed the targeted proteomics experiments. V.K., P.G. and M.B. contributed in data analysis and interpretation. T.C. and D.B. interpreted data. P.V. designed and supervised the study, performed data analysis, and wrote the manuscript.

Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity--infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)--we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.

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 ...

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