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  • Rockefeller University Press  (11)
  • Medicine  (11)
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  • Rockefeller University Press  (11)
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  • Medicine  (11)
RVK
  • 1
    Online Resource
    Online Resource
    Functional vulnerability of liver macrophages to capsules defines virulence of blood-borne bacteria
    Rockefeller University Press ; 2022
    In:  Journal of Experimental Medicine Vol. 219, No. 4 ( 2022-04-04)
    Details
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 219, No. 4 ( 2022-04-04)
    Abstract: Many encapsulated bacteria use capsules to cause invasive diseases. However, it remains largely unknown how the capsules enhance bacterial virulence under in vivo infection conditions. Here we show that the capsules primarily target the liver to enhance bacterial survival at the onset of blood-borne infections. In a mouse sepsis model, the capsules enabled human pathogens Streptococcus pneumoniae and Escherichia coli to circumvent the recognition of liver-resident macrophage Kupffer cells (KCs) in a capsular serotype-dependent manner. In contrast to effective capture of acapsular bacteria by KCs, the encapsulated bacteria are partially (low-virulence types) or completely (high-virulence types) “untouchable” for KCs. We finally identified the asialoglycoprotein receptor (ASGR) as the first known capsule receptor on KCs to recognize the low-virulence serotype-7F and -14 pneumococcal capsules. Our data identify the molecular interplay between the capsules and KCs as a master controller of the fate and virulence of encapsulated bacteria, and suggest that the interplay is targetable for therapeutic control of septic infections.
    Type of Medium: Online Resource
    ISSN: 0022-1007 , 1540-9538
    URL: Article
    DOI: 10.1084/jem.20212032
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2022
    detail.hit.zdb_id: 1477240-1
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  • 2
    Online Resource
    Online Resource
    B7DC/PDL2 Promotes Tumor Immunity by a PD-1–independent Mechanism
    Rockefeller University Press ; 2003
    In:  The Journal of Experimental Medicine Vol. 197, No. 12 ( 2003-06-16), p. 1721-1730
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 197, No. 12 ( 2003-06-16), p. 1721-1730
    Abstract: B7H1 (PDL1) and B7DC (PDL2) are two new members of the B7 family that can interact with PD-1, a putative negative regulator for immune function. Recent studies have provided evidence for inhibitory functions of both members via PD-1. Meanwhile, compelling evidence exists for costimulatory function of both members. Here we demonstrate that expression of B7DC on the tumor cells promotes CD8 T cell–mediated rejection of tumor cells, at both the induction and effector phase of antitumor immunity. Moreover, B7DC binds to PD-1(−/−) cells and enhances T cell killing in a PD-1–independent mechanism. Our results demonstrate a novel pathway for B7DC to promote tumor immunity and may reconcile the apparently contradictory findings on the function of B7DC.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.20022089
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2003
    detail.hit.zdb_id: 1477240-1
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  • 3
    Online Resource
    Online Resource
    Anti–IFN-γ autoantibodies underlie disseminated Talaromyces marneffei infections
    Rockefeller University Press ; 2020
    In:  Journal of Experimental Medicine Vol. 217, No. 12 ( 2020-12-07)
    Details
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 217, No. 12 ( 2020-12-07)
    Abstract: Talaromyces marneffei causes life-threatening opportunistic infections, mainly in Southeast Asia and South China. T. marneffei mainly infects patients with human immunodeficiency virus (HIV) but also infects individuals without known immunosuppression. Here we investigated the involvement of anti–IFN-γ autoantibodies in severe T. marneffei infections in HIV-negative patients. We enrolled 58 HIV-negative adults with severe T. marneffei infections who were otherwise healthy. We found a high prevalence of neutralizing anti–IFN-γ autoantibodies (94.8%) in this cohort. The presence of anti–IFN-γ autoantibodies was strongly associated with HLA-DRB1*16:02 and -DQB1*05:02 alleles in these patients. We demonstrated that adult-onset acquired immunodeficiency due to autoantibodies against IFN-γ is the major cause of severe T. marneffei infections in HIV-negative patients in regions where this fungus is endemic. The high prevalence of anti–IFN-γ autoantibody–associated HLA class II DRB1*16:02 and DQB1*05:02 alleles may account for severe T. marneffei infections in Southeast Asia. Our findings clarify the pathogenesis of T. marneffei infection and pave the way for developing novel treatments.
    Type of Medium: Online Resource
    ISSN: 0022-1007 , 1540-9538
    URL: Article
    DOI: 10.1084/jem.20190502
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2020
    detail.hit.zdb_id: 1477240-1
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  • 4
    Online Resource
    Online Resource
    The Requirement of Membrane Lymphotoxin for the Presence of Dendritic Cells in Lymphoid Tissues
    Rockefeller University Press ; 1999
    In:  The Journal of Experimental Medicine Vol. 190, No. 5 ( 1999-09-06), p. 629-638
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 190, No. 5 ( 1999-09-06), p. 629-638
    Abstract: Although several cytokines, including tumor necrosis factor (TNF), can promote the growth of dendritic cells (DCs) in vitro, the cytokines that naturally regulate DC development and function in vivo have not been well defined. Here, we report that membrane lymphotoxin (LT), instead of TNF, regulates the migration of DCs in the spleen. LTα−/− mice, lacking membrane LTα/β and LTα3, show markedly reduced numbers of DCs in the spleen. Unlike wild-type mice and TNF−/− mice that have densely clustered DCs in the T cell zone and around the marginal zone, splenic DCs in LTα−/− mice are randomly distributed. The reduced number of DCs in lymphoid tissues of LTα−/− mice is associated with an increased number of DCs in nonlymphoid tissues. The number of splenic DCs in LTα−/− mice is restored when additional LT-expressing cells are provided. Blocking membrane LTα/β in wild-type mice markedly diminishes the accumulation of DCs in lymphoid tissues. These data suggest that membrane LT is an essential ligand for the presence of DCs in the spleen. Mice deficient in TNF receptor, which is the receptor for both soluble LTα3 and TNF-α3 trimers, have normal numbers of DCs. However, LTβR−/− mice show reduced numbers of DCs, similar to the mice lacking membrane LT α/β. Taken together, these results support the notion that the signaling via LTβR by membrane LTα/β is required for the presence of DCs in lymphoid tissues.
    Type of Medium: Online Resource
    ISSN: 0022-1007 , 1540-9538
    URL: Article
    DOI: 10.1084/jem.190.5.629
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 1999
    detail.hit.zdb_id: 1477240-1
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  • 5
    Online Resource
    Online Resource
    Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
    Rockefeller University Press ; 2014
    In:  Journal of Experimental Medicine Vol. 211, No. 6 ( 2014-06-02), p. 1093-1108
    Details
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 211, No. 6 ( 2014-06-02), p. 1093-1108
    Abstract: Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment with AML cells (leukemic cells, LCs) results in an increase in survival and proliferation. We determined that TNF stimulation drives the JNK–AP1 pathway in a manner parallel to NF-κB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-κB inhibitor treatment by blocking the TNF–JNK–AP1 signaling pathway. Our data suggest that co-inhibition of both TNF–JNK–AP1 and NF-κB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.20130990
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2014
    detail.hit.zdb_id: 1477240-1
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  • 6
    Online Resource
    Online Resource
    The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis
    Rockefeller University Press ; 2005
    In:  The Journal of Experimental Medicine Vol. 202, No. 8 ( 2005-10-17), p. 1141-1151
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 202, No. 8 ( 2005-10-17), p. 1141-1151
    Abstract: The Scurfy mutation of the FoxP3 gene (FoxP3sf) in the mouse and analogous mutations in human result in lethal autoimmunity. The mutation of FoxP3 in the hematopoietic cells impairs the development of regulatory T cells. In addition, development of the Scurfy disease also may require mutation of the gene in nonhematopoietic cells. The T cell–extrinsic function of FoxP3 has not been characterized. Here we show that the FoxP3sf mutation leads to defective thymopoiesis, which is caused by inactivation of FoxP3 in the thymic stromal cells. FoxP3 mutation also results in overexpression of ErbB2 in the thymic stroma, which may be involved in defective thymopoiesis. Our data reveal a novel T cell–extrinsic function of FoxP3. In combination, the T cell–intrinsic and –extrinsic defects provide plausible explanation for the severity of the autoimmune diseases in the scurfy mice and in patients who have immunodysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.20050157
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2005
    detail.hit.zdb_id: 1477240-1
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  • 7
    Online Resource
    Online Resource
    Gata2 cis-element is required for hematopoietic stem cell generation in the mammalian embryo
    Rockefeller University Press ; 2013
    In:  Journal of Experimental Medicine Vol. 210, No. 13 ( 2013-12-16), p. 2833-2842
    Details
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 210, No. 13 ( 2013-12-16), p. 2833-2842
    Abstract: The generation of hematopoietic stem cells (HSCs) from hemogenic endothelium within the aorta, gonad, mesonephros (AGM) region of the mammalian embryo is crucial for development of the adult hematopoietic system. We described a deletion of a Gata2 cis-element (+9.5) that depletes fetal liver HSCs, is lethal at E13–14 of embryogenesis, and is mutated in an immunodeficiency that progresses to myelodysplasia/leukemia. Here, we demonstrate that the +9.5 element enhances Gata2 expression and is required to generate long-term repopulating HSCs in the AGM. Deletion of the +9.5 element abrogated the capacity of hemogenic endothelium to generate HSC-containing clusters in the aorta. Genomic analyses indicated that the +9.5 element regulated a rich ensemble of genes that control hemogenic endothelium and HSCs, as well as genes not implicated in hematopoiesis. These results reveal a mechanism that controls stem cell emergence from hemogenic endothelium to establish the adult hematopoietic system.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.20130733
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2013
    detail.hit.zdb_id: 1477240-1
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  • 8
    Online Resource
    Online Resource
    USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2
    Rockefeller University Press ; 2020
    In:  Journal of Experimental Medicine Vol. 217, No. 5 ( 2020-05-04)
    Details
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 217, No. 5 ( 2020-05-04)
    Abstract: USP22 is a cytoplasmic and nuclear deubiquitinating enzyme, and the functions of cytoplasmic USP22 are unclear. Here, we discovered that cytoplasmic USP22 promoted nuclear translocation of IRF3 by deubiquitianting and stabilizing KPNA2 after viral infection. Viral infection induced USP22-IRF3 association in the cytoplasm in a KPNA2-depedent manner, and knockdown or knockout of USP22 or KPNA2 impaired IRF3 nuclear translocation and expression of downstream genes after viral infection. Consistently, Cre-ER Usp22fl/fl or Lyz2-Cre Usp22fl/fl mice produced decreased levels of type I IFNs after viral infection and exhibited increased susceptibility to lethal viral infection compared with the respective control littermates. Mechanistically, USP22 deubiquitinated and stabilized KPNA2 after viral infection to facilitate efficient nuclear translocation of IRF3. Reconstitution of KPNA2 into USP22 knockout cells restored virus-triggered nuclear translocation of IRF3 and cellular antiviral responses. These findings define a previously unknown function of cytoplasmic USP22 and establish a mechanistic link between USP22 and IRF3 nuclear translocation that expands potential therapeutic strategies for infectious diseases.
    Type of Medium: Online Resource
    ISSN: 0022-1007 , 1540-9538
    URL: Article
    DOI: 10.1084/jem.20191174
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2020
    detail.hit.zdb_id: 1477240-1
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  • 9
    Online Resource
    Online Resource
    Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma
    Rockefeller University Press ; 2019
    In:  Journal of Experimental Medicine Vol. 216, No. 3 ( 2019-03-04), p. 656-673
    Details
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 216, No. 3 ( 2019-03-04), p. 656-673
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGFβ1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0022-1007 , 1540-9538
    URL: Article
    DOI: 10.1084/jem.20180749
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2019
    detail.hit.zdb_id: 1477240-1
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  • 10
    Online Resource
    Online Resource
    Perinatal Blockade of B7-1 and B7-2 Inhibits Clonal Deletion of Highly Pathogenic Autoreactive T Cells
    Rockefeller University Press ; 2002
    In:  The Journal of Experimental Medicine Vol. 195, No. 8 ( 2002-04-15), p. 959-971
    Details
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 195, No. 8 ( 2002-04-15), p. 959-971
    Abstract: A number of in vitro studies have suggested that costimulatory molecules B7-1 and B7-2 and their receptor CD28 can promote clonal deletion, and limited in vivo studies have indicated that CD28 is involved in the clonal deletion of some T cells. However, the significance of B7-mediated clonal deletion in preventing autoimmune diseases has not been studied systematically. Here we report that the perinatal blockade of B7-1 and B7-2 substantially inhibits the clonal deletion of T cells in the thymus and leads to an accumulation of T cells capable of inducing fatal multiorgan inflammation. These results reveal a critical role for costimulatory molecules B7-1 and B7-2 in deleting pathogenic autoreactive T cells in the thymus. The critical role of B7-1 and B7-2 in T cell clonal deletion may explain, at least in part, the paradoxical increase of autoimmune disease in mice deficient for this family of costimulatory molecules, such as cytotoxic T lymphocyte associated molecule 4, CD28, and B7-2. The strong pathogenicity of the self-reactive T cells supports a central hypothesis in immunology, which is that clonal deletion plays an important role in preventing autoimmune diseases.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.20011948
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2002
    detail.hit.zdb_id: 1477240-1
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