Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.

Abstract:

:Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8(+) T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intrahepatic myeloid-cell aggregates for T cell population expansion') without causing immunopathology. In the liver, CTL proliferation was restricted to iMATEs that were composed of inflammatory monocyte-derived CD11b(+) cells. Signaling via tumor-necrosis factor (TNF) caused iMATE formation that facilitated costimulation dependent on the receptor OX40 for expansion of the CTL population. The iMATEs arose during acute viral infection but were absent during chronic viral infection, yet they were still induced by TLR signaling. Such hepatic expansion of the CTL population controlled chronic viral infection of the liver after vaccination with DNA. Thus, iMATEs are dynamic structures that overcome regulatory cues that limit the population expansion of CTLs during chronic infection and can be used in new therapeutic vaccination strategies.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

Huang LR,Wohlleber D,Reisinger F,Jenne CN,Cheng RL,Abdullah Z,Schildberg FA,Odenthal M,Dienes HP,van Rooijen N,Schmitt E,Garbi N,Croft M,Kurts C,Kubes P,Protzer U,Heikenwalder M,Knolle PA

doi

10.1038/ni.2573

subject

Has Abstract

pub_date

2013-06-01 00:00:00

pages

574-83

issue

6

eissn

1529-2908

issn

1529-2916

pii

ni.2573

journal_volume

14

pub_type

杂志文章
  • Deciphering CD4+ T cell specificity using novel MHC-TCR chimeric receptors.

    abstract::αβ T cell antigen receptors (TCRs) bind complexes of peptide and major histocompatibility complex (pMHC) with low affinity, which poses a considerable challenge for the direct identification of αβ T cell cognate peptides. Here we describe a platform for the discovery of MHC class II epitopes based on the screening of ...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/s41590-019-0335-z

    authors: Kisielow J,Obermair FJ,Kopf M

    更新日期:2019-05-01 00:00:00

  • Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF-IRF4 transcription factor complex.

    abstract::Variable strengths of signaling via the T cell antigen receptor (TCR) can produce divergent outcomes, but the mechanism of this remains obscure. The abundance of the transcription factor IRF4 increases with TCR signal strength, but how this would induce distinct types of responses is unclear. We compared the expressio...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.3714

    authors: Iwata A,Durai V,Tussiwand R,Briseño CG,Wu X,Grajales-Reyes GE,Egawa T,Murphy TL,Murphy KM

    更新日期:2017-05-01 00:00:00

  • The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory.

    abstract::Immunological memory is thought to be mediated exclusively by lymphocytes. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection, which suggests the presence of innate immunological memory. Here we identified an important role for the stress-response transcrip...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.3257

    authors: Yoshida K,Maekawa T,Zhu Y,Renard-Guillet C,Chatton B,Inoue K,Uchiyama T,Ishibashi K,Yamada T,Ohno N,Shirahige K,Okada-Hatakeyama M,Ishii S

    更新日期:2015-10-01 00:00:00

  • The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors.

    abstract::The orphan nuclear receptor SHP (small heterodimer partner) is a transcriptional corepressor that regulates hepatic metabolic pathways. Here we identified a role for SHP as an intrinsic negative regulator of Toll-like receptor (TLR)-triggered inflammatory responses. SHP-deficient mice were more susceptible to endotoxi...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.2064

    authors: Yuk JM,Shin DM,Lee HM,Kim JJ,Kim SW,Jin HS,Yang CS,Park KA,Chanda D,Kim DK,Huang SM,Lee SK,Lee CH,Kim JM,Song CH,Lee SY,Hur GM,Moore DD,Choi HS,Jo EK

    更新日期:2011-07-03 00:00:00

  • The nuclear receptor LXRα controls the functional specialization of splenic macrophages.

    abstract::Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was ...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.2622

    authors: A-Gonzalez N,Guillen JA,Gallardo G,Diaz M,de la Rosa JV,Hernandez IH,Casanova-Acebes M,Lopez F,Tabraue C,Beceiro S,Hong C,Lara PC,Andujar M,Arai S,Miyazaki T,Li S,Corbi AL,Tontonoz P,Hidalgo A,Castrillo A

    更新日期:2013-08-01 00:00:00

  • Egr-2 and Egr-3 are negative regulators of T cell activation.

    abstract::T cell receptor engagement in the absence of proper accessory signals leads to T cell anergy. E3 ligases are involved in maintaining the anergic state. However, the specific molecules responsible for the induction of anergy have yet to be elucidated. Using microarray analysis we have identified here early growth respo...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni1193

    authors: Safford M,Collins S,Lutz MA,Allen A,Huang CT,Kowalski J,Blackford A,Horton MR,Drake C,Schwartz RH,Powell JD

    更新日期:2005-05-01 00:00:00

  • A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells.

    abstract::The molecular mechanisms directing the development of 'natural' CD4+CD25+Foxp3+ regulatory T cells (T(reg) cells) in the thymus are not thoroughly understood. We show here that conditional deletion of transforming growth factor-beta receptor I (TbetaRI) in T cells blocked the appearance of CD4+CD25+Foxp3+ thymocytes a...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.1607

    authors: Liu Y,Zhang P,Li J,Kulkarni AB,Perruche S,Chen W

    更新日期:2008-06-01 00:00:00

  • Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell induced inflammation.

    abstract::CD46 is a widely expressed transmembrane protein that was initially identified as binding and inactivating C3b and C4b complement products. We used mice that were transgenic for one of two human CD46 isoforms that differ in their cytoplasmic domains (termed CD46-1 and CD46-2) to analyze the effect of CD46 stimulation ...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni810

    authors: Marie JC,Astier AL,Rivailler P,Rabourdin-Combe C,Wild TF,Horvat B

    更新日期:2002-07-01 00:00:00

  • Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development.

    abstract::The catalytic activity of Zap70 is crucial for T cell antigen receptor (TCR) signaling, but the quantitative and temporal requirements for its function in thymocyte development are not known. Using a chemical-genetic system to selectively and reversibly inhibit Zap70 catalytic activity in a model of synchronized thymi...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.2918

    authors: Au-Yeung BB,Melichar HJ,Ross JO,Cheng DA,Zikherman J,Shokat KM,Robey EA,Weiss A

    更新日期:2014-07-01 00:00:00

  • Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57.

    abstract::The thiol-oxidoreductase ERp57 is an integral component of the peptide-loading complex of the major histocompatibility complex (MHC) class I pathway, but its function is unknown. To investigate its function in antigen presentation, we generated ERp57-deficient mice. Death in utero caused by ubiquitous ERp57 deletion w...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni1288

    authors: Garbi N,Tanaka S,Momburg F,Hämmerling GJ

    更新日期:2006-01-01 00:00:00

  • A microRNA upregulated in asthma airway T cells promotes TH2 cytokine production.

    abstract::MicroRNAs (miRNAs) exert powerful effects on immunological function by tuning networks of target genes that orchestrate cell activity. We sought to identify miRNAs and miRNA-regulated pathways that control the type 2 helper T cell (TH2 cell) responses that drive pathogenic inflammation in asthma. Profiling miRNA expre...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.3026

    authors: Simpson LJ,Patel S,Bhakta NR,Choy DF,Brightbill HD,Ren X,Wang Y,Pua HH,Baumjohann D,Montoya MM,Panduro M,Remedios KA,Huang X,Fahy JV,Arron JR,Woodruff PG,Ansel KM

    更新日期:2014-12-01 00:00:00

  • Publisher Correction: Transcription factor Hoxb5 reprograms B cells into functional T lymphocytes.

    abstract::In the version of this article initially published, some identification of the supplementary information was incorrect. The items originally called Supplementary Tables 1, 2, 3, 4 and 5 should be Source Data Figures 1, 2, 4, 5 and 7, respectively; those originally called Supplementary Tables 6, 7 and 8 should be Suppl...

    journal_title:Nature immunology

    pub_type: 已发布勘误

    doi:10.1038/s41590-018-0154-7

    authors: Zhang M,Dong Y,Hu F,Yang D,Zhao Q,Lv C,Wang Y,Xia C,Weng Q,Liu X,Li C,Zhou P,Wang T,Guan Y,Guo R,Liu L,Geng Y,Wu H,Du J,Hu Z,Xu S,Chen J,He A,Liu B,Wang D,Yang YG,Wang J

    更新日期:2018-09-01 00:00:00

  • Viral interference with antigen presentation.

    abstract::CD8+ T cells play an important role in immunity to viruses. Just how important these cells are is demonstrated by the evolution of viral strategies for blocking the generation or display of peptide-major histocompatibility complex class I complexes on the surfaces of virus-infected cells. Here, we focus on viral inter...

    journal_title:Nature immunology

    pub_type: 杂志文章,评审

    doi:10.1038/ni1102-1019

    authors: Yewdell JW,Hill AB

    更新日期:2002-11-01 00:00:00

  • TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentiation.

    abstract::Mice deficient in the adaptor Ndfip1 develop inflammation at sites of environmental antigen exposure. We show here that such mice had fewer inducible regulatory T cells (iT(reg) cells). In vitro, Ndfip1-deficient T cells expressed normal amounts of the transcription factor Foxp3 during the first 48 h of iT(reg) cell d...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.2154

    authors: Beal AM,Ramos-Hernández N,Riling CR,Nowelsky EA,Oliver PM

    更新日期:2011-11-13 00:00:00

  • E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1.

    abstract::TBK1 is essential for interferon-β (IFN-β) production and innate antiviral immunity. Here we identified the T cell anergy-related E3 ubiquitin ligase RNF128 as a positive regulator of TBK1 activation. RNF128 directly interacted with TBK1 through its protease-associated (PA) domain and catalyzed the K63-linked polyubiq...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.3588

    authors: Song G,Liu B,Li Z,Wu H,Wang P,Zhao K,Jiang G,Zhang L,Gao C

    更新日期:2016-12-01 00:00:00

  • Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance.

    abstract::CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)--a member of the tumor necrosis factor-nerve growth factor (TNF-NGF) receptor gen...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni759

    authors: Shimizu J,Yamazaki S,Takahashi T,Ishida Y,Sakaguchi S

    更新日期:2002-02-01 00:00:00

  • The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.

    abstract::Tim-3 is a T helper type 1 (T(H)1)-specific cell surface molecule that seems to regulate T(H)1 responses and the induction of peripheral tolerance. However, the identity of the Tim-3 ligand and the mechanism by which this ligand inhibits the function of effector T(H)1 cells remain unknown. Here we show that galectin-9...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni1271

    authors: Zhu C,Anderson AC,Schubart A,Xiong H,Imitola J,Khoury SJ,Zheng XX,Strom TB,Kuchroo VK

    更新日期:2005-12-01 00:00:00

  • Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production.

    abstract::Double-stranded DNA (dsDNA) in the cytoplasm triggers the production of interleukin 1β (IL-1β) as an antiviral host response, and deregulation of the pathways involved can promote inflammatory disease. Here we report a direct cytosolic interaction between the DNA-damage sensor Rad50 and the innate immune system adapto...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.2888

    authors: Roth S,Rottach A,Lotz-Havla AS,Laux V,Muschaweckh A,Gersting SW,Muntau AC,Hopfner KP,Jin L,Vanness K,Petrini JH,Drexler I,Leonhardt H,Ruland J

    更新日期:2014-06-01 00:00:00

  • Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.

    abstract::Naturally arising CD25(+)CD4(+) regulatory T cells actively maintain immunological self-tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish ...

    journal_title:Nature immunology

    pub_type: 杂志文章,评审

    doi:10.1038/ni1178

    authors: Sakaguchi S

    更新日期:2005-04-01 00:00:00

  • Somatic mutation hotspots correlate with DNA polymerase eta error spectrum.

    abstract::Mutational spectra analysis of 15 immunoglobulin genes suggested that consensus motifs RGYW and WA were universal descriptors of somatic hypermutation. Highly mutable sites, "hotspots", that matched WA were preferentially found in one DNA strand and RGYW hotspots were found in both strands. Analysis of base-substituti...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/88732

    authors: Rogozin IB,Pavlov YI,Bebenek K,Matsuda T,Kunkel TA

    更新日期:2001-06-01 00:00:00

  • Different molecular complexes that mediate transcriptional induction and repression by FoxP3.

    abstract::FoxP3 conditions the transcriptional signature and functional facets of regulatory T cells (Treg cells). Its mechanism of action, whether as an activator or a repressor, has remained unclear. Here, chromatin analysis showed that FoxP3 bound active enhancer elements, not repressed chromatin, around loci over- or under-...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.3835

    authors: Kwon HK,Chen HM,Mathis D,Benoist C

    更新日期:2017-11-01 00:00:00

  • Renaissance for mouse models of human hematopoiesis and immunobiology.

    abstract::More than 20 years after the first successful engraftment of human leukocytes and hematopoietic organs in mice, scientists met for the 2nd International Workshop on Humanized Mice to discuss progress and to highlight expectations in this dynamic field. ...

    journal_title:Nature immunology

    pub_type: 杂志文章,评审

    doi:10.1038/ni1009-1039

    authors: Manz MG,Di Santo JP

    更新日期:2009-10-01 00:00:00

  • IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.

    abstract::We report here the identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state. Three closely positioned genes on human chromosome 19 encode distinct but paralogous proteins, which we designate interferon-lambda1 (IFN-lambda1), IFN-lambda2 and IFN-lambda3 (tentati...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni875

    authors: Kotenko SV,Gallagher G,Baurin VV,Lewis-Antes A,Shen M,Shah NK,Langer JA,Sheikh F,Dickensheets H,Donnelly RP

    更新日期:2003-01-01 00:00:00

  • IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor.

    abstract::CD8+ T cell exhaustion dampens antitumor immunity. Although several transcription factors have been identified that regulate T cell exhaustion, the molecular mechanisms by which CD8+ T cells are triggered to enter an exhausted state remain unclear. Here, we show that interleukin-2 (IL-2) acts as an environmental cue t...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/s41590-020-00850-9

    authors: Liu Y,Zhou N,Zhou L,Wang J,Zhou Y,Zhang T,Fang Y,Deng J,Gao Y,Liang X,Lv J,Wang Z,Xie J,Xue Y,Zhang H,Ma J,Tang K,Fang Y,Cheng F,Zhang C,Dong B,Zhao Y,Yuan P,Gao Q,Zhang H,Xiao-Feng Qin F,Huang B

    更新日期:2021-01-11 00:00:00

  • Control of the innate immune response by the mevalonate pathway.

    abstract::Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-transl...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.3487

    authors: Akula MK,Shi M,Jiang Z,Foster CE,Miao D,Li AS,Zhang X,Gavin RM,Forde SD,Germain G,Carpenter S,Rosadini CV,Gritsman K,Chae JJ,Hampton R,Silverman N,Gravallese EM,Kagan JC,Fitzgerald KA,Kastner DL,Golenbock DT,Ber

    更新日期:2016-08-01 00:00:00

  • The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells.

    abstract::CD4(+) follicular helper T cells (T(FH) cells) are essential for germinal center (GC) responses and long-lived antibody responses. Here we report that naive CD4(+) T cells deficient in the transcription factor Foxp1 'preferentially' differentiated into T(FH) cells, which resulted in substantially enhanced GC and antib...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.2890

    authors: Wang H,Geng J,Wen X,Bi E,Kossenkov AV,Wolf AI,Tas J,Choi YS,Takata H,Day TJ,Chang LY,Sprout SL,Becker EK,Willen J,Tian L,Wang X,Xiao C,Jiang P,Crotty S,Victora GD,Showe LC,Tucker HO,Erikson J,Hu H

    更新日期:2014-07-01 00:00:00

  • Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses.

    abstract::The present vaccine against influenza virus has the inevitable risk of antigenic discordance between the vaccine and the circulating strains, which diminishes vaccine efficacy. This necessitates new approaches that provide broader protection against influenza. Here we designed a vaccine using the hypervariable recepto...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/s41590-018-0305-x

    authors: Kanekiyo M,Joyce MG,Gillespie RA,Gallagher JR,Andrews SF,Yassine HM,Wheatley AK,Fisher BE,Ambrozak DR,Creanga A,Leung K,Yang ES,Boyoglu-Barnum S,Georgiev IS,Tsybovsky Y,Prabhakaran MS,Andersen H,Kong WP,Baxa U,Zephi

    更新日期:2019-03-01 00:00:00

  • Infection of dendritic cells by murine cytomegalovirus induces functional paralysis.

    abstract::Cytomegalovirus (CMV), measles and HIV are the main human pathogens known to induce immunosuppression. Unlike measles and HIV, and despite the availability of a well studied animal model, little is known about the mechanisms that control CMV-induced immunosuppression. We hypothesized that dendritic cells (DCs), which ...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni724

    authors: Andrews DM,Andoniou CE,Granucci F,Ricciardi-Castagnoli P,Degli-Esposti MA

    更新日期:2001-11-01 00:00:00

  • CCL19-CCR7-dependent reverse transendothelial migration of myeloid cells clears Chlamydia muridarum from the arterial intima.

    abstract::Regions of the normal arterial intima predisposed to atherosclerosis are sites of ongoing monocyte trafficking and also contain resident myeloid cells with features of dendritic cells. However, the pathophysiological roles of these cells are poorly understood. Here we found that intimal myeloid cells underwent reverse...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.3564

    authors: Roufaiel M,Gracey E,Siu A,Zhu SN,Lau A,Ibrahim H,Althagafi M,Tai K,Hyduk SJ,Cybulsky KO,Ensan S,Li A,Besla R,Becker HM,Xiao H,Luther SA,Inman RD,Robbins CS,Jongstra-Bilen J,Cybulsky MI

    更新日期:2016-11-01 00:00:00

  • Fc receptor gamma-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils.

    abstract::The Fc receptor common gamma-chain (FcRgamma) is a widely expressed adaptor bearing an immunoreceptor tyrosine-based activation motif (ITAM) that transduces activation signals from various immunoreceptors. We show here that basophils lacking FcRgamma developed normally and proliferated efficiently in response to inter...

    journal_title:Nature immunology

    pub_type: 杂志文章

    doi:10.1038/ni.1686

    authors: Hida S,Yamasaki S,Sakamoto Y,Takamoto M,Obata K,Takai T,Karasuyama H,Sugane K,Saito T,Taki S

    更新日期:2009-02-01 00:00:00