Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling

Xing, Yan; Wang, Xiaodan; Jameson, Stephen C.; Hogquist, Kristin A.

doi:10.1038/ni.3419

Cited by 169 publications

(226 citation statements)

References 53 publications

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“…At the SP stage, Pmel-iPSC-derived extrathymic T cells demonstrated variable expression of CD8β and CD62L relative to endogenous thymocytes, and expression of the MHC class I complex was dramatically reduced (Figures 1C and 1D). Expression of the MHC class I complex marks a developmental turning point, dividing immature thymocytes from mature, proliferation-competent SP thymocytes (Xing et al, 2016). Therefore, our results indicated that extrathymic T cells differentiated using the current OP9/DLL1 system exhibit a developmental divergence from endogenous T cells during the DP-to CD8αSP-transition.…”

Section: Resultsmentioning

confidence: 99%

“…To identify global transcriptional gene expression signatures, we analyzed activated signaling pathways and upstream regulators in iTEs versus extrathymic T cells using gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) (Figures 4D and S5A and S5B). GSEA identified enrichment of signaling pathways associated with positive selection and endogenous recent thymic emigrant (RTE) development, including the activation of IFN, nuclear factor κB (NF-κB), and TNF pathways and down-regulation of E2F signaling pathways (Figures 5A and S5A; Table S3; Carpenter and Bosselut, 2010; Xing et al, 2016). IPA showed an enrichment of similar regulatory pathways in iTEs, including activation of IFN pathway genes, as well as activation or inhibition of upstream regulators correlating to changes in activity that have been associated with late-stage thymocyte maturation (Figure S5B; Xing et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…GSEA identified enrichment of signaling pathways associated with positive selection and endogenous recent thymic emigrant (RTE) development, including the activation of IFN, nuclear factor κB (NF-κB), and TNF pathways and down-regulation of E2F signaling pathways (Figures 5A and S5A; Table S3; Carpenter and Bosselut, 2010; Xing et al, 2016). IPA showed an enrichment of similar regulatory pathways in iTEs, including activation of IFN pathway genes, as well as activation or inhibition of upstream regulators correlating to changes in activity that have been associated with late-stage thymocyte maturation (Figure S5B; Xing et al, 2016). Thus, iTEs exhibited transcriptional profiles observed in late stages of thymic maturation and RTE development.…”

Section: Resultsmentioning

confidence: 99%

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Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

et al. 2018

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SUMMARY Induced pluripotent stem cell (iPSC)-derived T cells may provide future therapies for cancer patients, but those generated by current methods, such as the OP9/DLL1 system, have shown abnormalities that pose major barriers for clinical translation. Our data indicate that these iPSC-derived CD8 single-positive T cells are more like CD4+CD8+ double-positive T cells than mature naive T cells because they display phenotypic markers of developmental arrest and an innate-like phenotype after stimulation. We developed a 3D thymic culture system to avoid these aberrant developmental fates, generating a homogeneous subset of CD8ab+ antigen-specific T cells, designated iPSC-derived thymic emigrants (iTEs). iTEs exhibit phenotypic and functional similarities to naive T cells both in vitro and in vivo, including the capacity for expansion, memory formation, and tumor suppression. These data illustrate the limitations of current methods and provide a tool to develop the next generation of iPSC-based antigen-specific immunotherapies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

et al. 2018

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“…The NF-kB pathway plays important roles in positive selection and postselection maturation (40,49). Moreover, many components of the NF-kB pathway have been reported to be SUMO targets (50).…”

Section: Discussionmentioning

confidence: 99%

“…These mice showed impaired production of mature SP thymocytes and failure of downregulation of CD69/HSA at the SP stage (38,39). Moreover, recently it was reported that NF-kB is involved in the late stages of T cell maturation in the thymus (40).We thus asked whether posttranslational modification or downstream target activity of these proteins was regulated by Ubc9-mediated SUMOylation pathway during positive selection. Themis, however, could not be modified by SUMO even if overexpressed together with SUMO1/2 and UBC9 in 293T cells (Supplemental Fig.…”

Section: Tcr-induced Nfat Nuclear Localization Is Regulated By Sumoylmentioning

confidence: 98%

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

Wang

Ding

Demarque

et al. 2017

The Journal of Immunology

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SUMOylation is an important posttranslational modification that regulates protein function in diverse biological processes. However, its role in early T cell development has not been genetically studied. UBC9 is the only E2 enzyme for all SUMOylation. In this study, by selectively deleting Ubc9 gene in T cells, we have investigated the functional roles of SUMOylation in T cell development. Loss of Ubc9 results in a significant reduction of CD4 and CD8 single-positive lymphocytes in both thymus and periphery. Ubc9-deficient cells exhibit defective late-stage maturation post the initial positive selection with increased apoptosis and impaired proliferation, among which attenuated IL-7 signaling was correlated with the decreased survival of Ubc9-deficent CD8 single-positive cells. Furthermore, NFAT nuclear retention induced by TCR signals was regulated by SUMOylation during thymocytes development. Our study thus reveals a novel posttranslational mechanism underlying T cell development.

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Augmentation of Stimulator of Interferon Genes–Induced Type I Interferon Production in COPA Syndrome

Kato

Yamamoto

Honda

et al. 2021

Arthritis & Rheumatology

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Objective Coatomer subunit alpha (COPA) syndrome, also known as autoinflammatory interstitial lung, joint, and kidney disease, is caused by heterozygous mutations in COPA. We identified a novel COPA variant in 4 patients in one family. We undertook this study to elucidate whether and how the variant causes manifestations of COPA syndrome by studying these 4 patients and by analyzing results from a gene‐targeted mouse model. Methods We performed whole‐exome sequencing in 7 family members and measured the type I interferon (IFN) signature of the peripheral blood cells. We analyzed the effects of COPA variants in in vitro experiments and in Copa mutant mice that were generated. Results We identified a heterozygous variant of COPA (c.725T>G, p.Val242Gly) in the 4 affected members of the family. The IFN score was high in the members carrying the variant. In vitro analysis revealed that COPA V242G, as well as the previously reported disease‐causing variants, augmented stimulator of interferon genes (STING)–induced type I IFN promoter activities. CopaV242G/+ mice manifested interstitial lung disease and STING‐dependent elevation of IFN‐stimulated gene expression. In CopaV242G/+ dendritic cells, the STING pathway was not constitutively activated but was hyperactivated upon stimulation, leading to increased type I IFN production. Conclusion V242G, a novel COPA variant, was found in 4 patients from one family. In gene‐targeted mice with the V242G variant, interstitial lung disease was recapitulated and augmented responses of the STING pathway, leading to an increase in type I IFN production, were demonstrated.

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Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling

Cited by 169 publications

References 53 publications

Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

Augmentation of Stimulator of Interferon Genes–Induced Type I Interferon Production in COPA Syndrome

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