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Arkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation

Xu, Hao; Wu, Lin; Nguyen, Henry H; Mesa, Kailin R; Raghavan, Varsha; Episkopou, Vasso; Littman, Dan R
TGF-β 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-β signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), an E3 ubiquitin ligase that mediates TGF-β signaling during development. Inactivation of Arkadia in CD4+ T cells resulted in impaired Treg cell differentiation in vitro and loss of RORγt+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-β signaling modules governing Th17 and iTreg cell differentiation programs that could be targeted to selectively modulate T cell functions.
PMCID:8421263
PMID: 34473197
ISSN: 1540-9538
CID: 5061152

Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians

Sato, Yuko; Atarashi, Koji; Plichta, Damian R; Arai, Yasumichi; Sasajima, Satoshi; Kearney, Sean M; Suda, Wataru; Takeshita, Kozue; Sasaki, Takahiro; Okamoto, Shoki; Skelly, Ashwin N; Okamura, Yuki; Vlamakis, Hera; Li, Youxian; Tanoue, Takeshi; Takei, Hajime; Nittono, Hiroshi; Narushima, Seiko; Irie, Junichiro; Itoh, Hiroshi; Moriya, Kyoji; Sugiura, Yuki; Suematsu, Makoto; Moritoki, Nobuko; Shibata, Shinsuke; Littman, Dan R; Fischbach, Michael A; Uwamino, Yoshifumi; Inoue, Takashi; Honda, Akira; Hattori, Masahira; Murai, Tsuyoshi; Xavier, Ramnik J; Hirose, Nobuyoshi; Honda, Kenya
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 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH) 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.
PMID: 34325466
ISSN: 1476-4687
CID: 4979772

c-MAF-dependent perivascular macrophages regulate diet-induced metabolic syndrome

Moura Silva, Hernandez; Kitoko, Jamil Zola; Queiroz, Camila Pereira; Kroehling, Lina; Matheis, Fanny; Yang, Katharine Lu; Reis, Bernardo S; Ren-Fielding, Christine; Littman, Dan R; Bozza, Marcelo Torres; Mucida, Daniel; Lafaille, Juan J
[Figure: see text].
PMID: 34597123
ISSN: 2470-9468
CID: 5061682

Arkadia-SKI/SnoN signaling differentially regulates TGF-beta-induced iTreg and Th17 cell differentiation

Xu, H; Wu, L; Nguyen, H H; Mesa, K R; Raghavan, V; Episkopou, V; Littman, D R
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.
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EMBASE:2014922086
ISSN: 0022-1007
CID: 5025972

Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes

Sano, Teruyuki; Kageyama, Takahiro; Fang, Victoria; Kedmi, Ranit; Martinez, Carlos Serafin; Talbot, Jhimmy; Chen, Alessandra; Cabrera, Ivan; Gorshko, Oleksandra; Kurakake, Reina; Yang, Yi; Ng, Charles; Schwab, Susan R; Littman, Dan R
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 β7. Stat3-dependent induction of RORγt, 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.
PMID: 34433045
ISSN: 2211-1247
CID: 4989122

Lung eosinophils elicited during allergic and acute aspergillosis express RORϪt and IL-23R but do not require IL-23 for IL-17 production

Yadav, Bhawna; Specht, Charles A.; Lee, Chrono K.; Pokrovskii, Maria; Huh, Jun R.; Littman, Dan R.; Levitz, Stuart M.
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 RORϪt with eosinophil IL-17 expression. Following A. fumigatus stimulation, a population of lung eosinophils expressed RORϪt, the master transcription factor for IL-17 regulation. Eosinophil RORϪt expression was demonstrated by flow cytometry, confocal microscopy, western blotting and an mCherry reporter mouse. Both nuclear and cytoplasmic localization of RORϪt 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 RORϪt, expression of RORϪt 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, RORϪt and IL-23R. However, IL-23 is dispensable for production of IL-17 and RORϪt.
SCOPUS:85114432014
ISSN: 1553-7366
CID: 5008822

SPNS2 enables T cell egress from lymph nodes during an immune response

Okuniewska, Martyna; Fang, Victoria; Baeyens, Audrey; Raghavan, Varsha; Lee, June-Yong; Littman, Dan R; Schwab, Susan R
T cell expression of sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) enables T cell exit from lymph nodes (LNs) into lymph, while endothelial S1PR1 expression regulates vascular permeability. Drugs targeting S1PR1 treat autoimmune disease by trapping pathogenic T cells within LNs, but they have adverse cardiovascular side effects. In homeostasis, the transporter SPNS2 supplies lymph S1P and enables T 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 T 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.
PMCID:8351797
PMID: 34260944
ISSN: 2211-1247
CID: 4965312

Immune cell control of nutrient absorption [Comment]

Talbot, Jhimmy; Littman, Dan R
PMID: 33737473
ISSN: 1095-9203
CID: 4836132

Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease

Lee, June-Yong; Hall, Jason A; Kroehling, Lina; Wu, Lin; Najar, Tariq; Nguyen, Henry H; Lin, Woan-Yu; Yeung, Stephen T; Silva, Hernandez Moura; Li, Dayi; Hine, Ashley; Loke, P'ng; Hudesman, David; Martin, Jerome C; Kenigsberg, Ephraim; Merad, Miriam; Khanna, Kamal M; Littman, Dan R
PMID: 33357400
ISSN: 1097-4172
CID: 4731172

Niche-Selective Inhibition of Pathogenic Th17 Cells by Targeting Metabolic Redundancy

Wu, Lin; Hollinshead, Kate E R; Hao, Yuhan; Au, Christy; Kroehling, Lina; Ng, Charles; Lin, Woan-Yu; Li, Dayi; Silva, Hernandez Moura; Shin, Jong; Lafaille, Juan J; Possemato, Richard; Pacold, Michael E; Papagiannakopoulos, Thales; Kimmelman, Alec C; Satija, Rahul; Littman, Dan R
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 T 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.
PMID: 32615085
ISSN: 1097-4172
CID: 4504552