Arkadia-SKI/SnoN signaling differentially regulates TGF-Î²-induced iTreg and Th17 cell differentiation
TGF-Î² signaling is fundamental for both Th17 and regulatory T (Treg) cell differentiation. However, these cells differ in requirements for downstream signaling components, such as SMAD effectors. To further characterize mechanisms that distinguish TGF-Î² signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), an E3 ubiquitin ligase that mediates TGF-Î² signaling during development. Inactivation of Arkadia in CD4+ T cells resulted in impaired Treg cell differentiation in vitro and loss of RORÎ³t+FOXP3+ iTreg cells in the intestinal lamina propria, which increased susceptibility to microbiota-induced mucosal inflammation. In contrast, Arkadia was dispensable for Th17 cell responses. Furthermore, genetic ablation of two Arkadia substrates, the transcriptional corepressors SKI and SnoN, rescued Arkadia-deficient iTreg cell differentiation both in vitro and in vivo. These results reveal distinct TGF-Î² signaling modules governing Th17 and iTreg cell differentiation programs that could be targeted to selectively modulate T cell functions.
Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians
Centenarians display decreased susceptibility to ageing-associated illness, chronic inflammation, and infectious disease1-3. Here we show that centenarians have a distinct gut microbiome enriched in microbes capable of generating unique secondary bile acids (BAs), including iso-, 3-oxo-, allo-, 3-oxoallo-, and isoallo-lithocholic acid (LCA). Among these BAs, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from a centenarian's faecal microbiota, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5Î±-reductase (5AR) and 3Î²-hydroxysteroid dehydrogenase (3Î²HSDH) were responsible for isoalloLCA production. IsoalloLCA exerted potent antimicrobial effects against gram-positive (but not gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that specific bile acid metabolism may be involved in reducing the risk of pathobiont infection, thereby potentially contributing to the maintenance of intestinal homeostasis.
c-MAF-dependent perivascular macrophages regulate diet-induced metabolic syndrome
[Figure: see text].
Arkadia-SKI/SnoN signaling differentially regulates TGF-beta-induced iTreg and Th17 cell differentiation
TGF-beta signaling is fundamental for both Th17 and regulatory T (Treg) cell differentiation. However, these cells differ in requirements for downstream signaling components, such as SMAD effectors. To further characterize mechanisms that distinguish TGF-beta signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), an E3 ubiquitin ligase that mediates TGF-beta signaling during development. Inactivation of Arkadia in CD4+ T cells resulted in impaired Treg cell differentiation in vitro and loss of RORgammat+FOXP3+ iTreg cells in the intestinal lamina propria, which increased susceptibility to microbiota-induced mucosal inflammation. In contrast, Arkadia was dispensable for Th17 cell responses. Furthermore, genetic ablation of two Arkadia substrates, the transcriptional corepressors SKI and SnoN, rescued Arkadia-deficient iTreg cell differentiation both in vitro and in vivo. These results reveal distinct TGF-beta signaling modules governing Th17 and iTreg cell differentiation programs that could be targeted to selectively modulate T cell functions.
Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes
Differentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here, we show that intestine-draining mesenteric lymph nodes (MLNs), not intestine proper, are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their upregulation of integrin Î²7. Stat3-dependent induction of RORÎ³t, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLNs and accumulation of the cells in the lamina propria.
Lung eosinophils elicited during allergic and acute aspergillosis express RORÏªt and IL-23R but do not require IL-23 for IL-17 production
Exposure to the mold, Aspergillus, is ubiquitous and generally has no adverse consequences in immunocompetent persons. However, invasive and allergic aspergillosis can develop in immunocompromised and atopic individuals, respectively. Previously, we demonstrated that mouse lung eosinophils produce IL-17 in response to stimulation by live conidia and antigens of A. fumigatus. Here, we utilized murine models of allergic and acute pulmonary aspergillosis to determine the association of IL-23, IL-23R and RORÏªt with eosinophil IL-17 expression. Following A. fumigatus stimulation, a population of lung eosinophils expressed RORÏªt, the master transcription factor for IL-17 regulation. Eosinophil RORÏªt expression was demonstrated by flow cytometry, confocal microscopy, western blotting and an mCherry reporter mouse. Both nuclear and cytoplasmic localization of RORÏªt in eosinophils were observed, although the former predominated. A population of lung eosinophils also expressed IL-23R. While expression of IL-23R was positively correlated with expression of RORÏªt, expression of RORÏªt and IL-17 was similar when comparing lung eosinophils from A. fumigatus-challenged wild-type and IL23p19-/- mice. Thus, in allergic and acute models of pulmonary aspergillosis, lung eosinophils express IL-17, RORÏªt and IL-23R. However, IL-23 is dispensable for production of IL-17 and RORÏªt.
SPNS2 enables TÂ cell egress from lymph nodes during an immune response
T cell expression of sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) enables TÂ cell exit from lymph nodes (LNs) into lymph, while endothelial S1PR1 expression regulates vascular permeability. Drugs targeting S1PR1 treat autoimmune disease by trapping pathogenic TÂ cells within LNs, but they have adverse cardiovascular side effects. In homeostasis, the transporter SPNS2 supplies lymph S1P and enables TÂ cell exit, while the transporter MFSD2B supplies most blood S1P and supports vascular function. It is unknown whether SPNS2 remains necessary to supply lymph S1P during an immune response, or whether in inflammation other compensatory transporters are upregulated. Here, using a model of dermal inflammation, we demonstrate that SPNS2 supplies the S1P that guides TÂ cells out of LNs with an ongoing immune response. Furthermore, deletion of Spns2 is protective in a mouse model of multiple sclerosis. These results support the therapeutic potential of SPNS2 inhibitors to achieve spatially specific modulation of S1P signaling.
Immune cell control of nutrient absorption [Comment]
Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease
Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy
Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in TÂ cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. In homeostatic Th17 cells, partial blockade of glycolysis upon Gpi1 inactivation was compensated by pentose phosphate pathway flux and increased mitochondrial respiration. In contrast, inflammatory Th17 cells experience a hypoxic microenvironment known to limit mitochondrial respiration, which is incompatible with loss of Gpi1. Our study suggests that inhibiting glycolysis by targeting Gpi1 could be an effective therapeutic strategy with minimum toxicity for Th17-mediated autoimmune diseases, and, more generally, that metabolic redundancies can be exploited for selective targeting of disease processes.