Immune control of infections with viruses or intracellular bacteria relies on cytotoxic CD8(+) T cells that use granzyme B (GzmB) for elimination of infected cells. During inflammation, mature antigen-presenting dendritic cells instruct naive T cells within lymphoid organs to develop into effector T cells. Here, we report a mechanistically distinct and more rapid process of effector T cell development occurring within 18 hr. Such rapid acquisition of effector T cell function occurred through cross-presenting liver sinusoidal endothelial cells (LSECs) in the absence of innate immune stimulation and known costimulatory signaling. Rather, interleukin-6 (IL-6) trans-signaling was required and sufficient for rapid induction of GzmB expression in CD8(+) T cells. Such LSEC-stimulated GzmB-expressing CD8(+) T cells further responded to inflammatory cytokines, eliciting increased and protracted effector functions. Our findings identify a role for IL-6 trans-signaling in rapid generation of effector function in CD8(+) T cells that may be beneficial for vaccination strategies.

As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important role in immune regulation besides its requirement for xenobiotic metabolism. Transcriptional activation of AhR target genes is counterregulated by the AhR repressor (AhRR) but the exact function of the AhRR in vivo is currently unknown. We here show that the AhRR is predominantly expressed in immune cells of the skin and intestine, different from other AhR target genes. Whereas AhRR antagonizes the anti-inflammatory function of the AhR in the context of systemic endotoxin shock, AhR and AhRR act in concert to dampen intestinal inflammation. Specifically, AhRR contributes to the maintenance of colonic intraepithelial lymphocytes and prevents excessive IL-1β production and Th17/Tc17 differentiation. In contrast, the AhRR enhances IFN-γ-production by effector T cells in the inflamed gut. Our findings highlight the physiologic importance of cell-type specific balancing of AhR/AhRR expression in response to microbial, nutritional and other environmental stimuli.

Development of CD8(+) T cell (CTL) immunity or tolerance is linked to the conditions during T cell priming. Dendritic cells (DCs) matured during inflammation generate effector/memory T cells, whereas immature DCs cause T cell deletion/anergy. We identify a third outcome of T cell priming in absence of inflammation enabled by cross-presenting liver sinusoidal endothelial cells. Such priming generated memory T cells that were spared from deletion by immature DCs. Similar to central memory T cells, liver-primed T cells differentiated into effector CTLs upon antigen re-encounter on matured DCs even after prolonged absence of antigen. Their reactivation required combinatorial signaling through the TCR, CD28, and IL-12R and controlled bacterial and viral infections. Gene expression profiling identified liver-primed T cells as a distinct Neuropilin-1(+) memory population. Generation of liver-primed memory T cells may prevent pathogens that avoid DC maturation by innate immune escape from also escaping adaptive immunity through attrition of the T cell repertoire.

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 ...

A diet rich in vegetables and fruit is generally considered healthy because of a high content of phytochemicals, vitamins, and fiber. The phytochemical indole-3-carbinol (I3C), a derivative of glucobrassicin, is sold as a dietary supplement promising diverse health benefits. I3C metabolites act as ligands of the aryl hydrocarbon receptor (AhR), an important sensor for environmental polyaromatic chemicals. Here, we investigated how dietary AhR ligand supplementation influences AhR target gene expression and intestinal microbiota composition. For this, we used AhR repressor (AhRR)-reporter mice as a tool to study AhR activation in the intestine following dietary I3C-supplementation in comparison with AhR ligand-deprived diets, including a high fat diet. AhRR expression in intestinal immune cells was mainly driven by dietary AhR ligands and was independent of microbial metabolites. A lack of dietary AhR ligands caused enhanced susceptibility to dextran sodium sulfate (DSS)-induced colitis and correlated with the expansion of Enterobacteriaceae, whereas Clostridiales, Muribaculaceae, and Rikenellaceae were strongly reduced. I3C supplementation largely reverted this effect. Comparison of I3C-induced changes in microbiota composition using wild-type (WT), AhRR-deficient, and AhR-deficient mice revealed both AhR-dependent and -independent alterations in the microbiome. Overall, our study demonstrates that dietary AhR ligand supplementation has a profound influence on Ahrr expression in intestinal immune cells as well as microbiota composition.