Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 62
Filter
1.
Immunity ; 48(3): 570-583.e8, 2018 03 20.
Article in English | MEDLINE | ID: mdl-29562203

ABSTRACT

Polymorphisms in NFKB1 that diminish its expression have been linked to human inflammatory diseases and increased risk for epithelial cancers. The underlying mechanisms are unknown, and the link is perplexing given that NF-κB signaling reportedly typically exerts pro-tumorigenic activity. Here we have shown that NF-κB1 deficiency, even loss of a single allele, resulted in spontaneous invasive gastric cancer (GC) in mice that mirrored the histopathological progression of human intestinal-type gastric adenocarcinoma. Bone marrow chimeras revealed that NF-κB1 exerted tumor suppressive functions in both epithelial and hematopoietic cells. RNA-seq analysis showed that NF-κB1 deficiency resulted in aberrant JAK-STAT signaling, which dysregulated expression of effectors of inflammation, antigen presentation, and immune checkpoints. Concomitant loss of STAT1 prevented these immune abnormalities and GC development. These findings provide mechanistic insight into how polymorphisms that attenuate NFKB1 expression predispose humans to epithelial cancers, highlighting the pro-tumorigenic activity of STAT1 and identifying targetable vulnerabilities in GC.


Subject(s)
Gene Expression Regulation, Neoplastic , Inflammation/genetics , Inflammation/metabolism , NF-kappa B/deficiency , STAT1 Transcription Factor/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Animals , Antigen Presentation/immunology , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Disease Models, Animal , Epithelial Cells/metabolism , Epithelial Cells/pathology , Gene Regulatory Networks , Humans , Inflammation/pathology , Mice , Mice, Knockout , STAT1 Transcription Factor/deficiency , Stomach Neoplasms/immunology , Stomach Neoplasms/pathology
2.
Nat Immunol ; 15(1): 15-25, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24352326

ABSTRACT

The NF-κB signal transduction pathway is best known as a major regulator of innate and adaptive immune responses, yet there is a growing appreciation of its importance in immune cell development, particularly of T lineage cells. In this Review, we discuss how the temporal regulation of NF-κB controls the stepwise differentiation and antigen-dependent selection of conventional and specialized subsets of T cells in response to T cell receptor and costimulatory, cytokine and growth factor signals.


Subject(s)
NF-kappa B/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , Thymocytes/immunology , Cell Lineage/immunology , Humans , Models, Immunological , NF-kappa B/metabolism , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Thymocytes/cytology , Thymocytes/metabolism
4.
Eur J Immunol ; 51(8): 2006-2026, 2021 08.
Article in English | MEDLINE | ID: mdl-33960413

ABSTRACT

The NF-κB transcription factor c-Rel is a critical regulator of Treg ontogeny, controlling multiple points of the stepwise developmental pathway. Here, we found that the thymic Treg defect in c-Rel-deficient (cRel-/- ) mice is quantitative, not qualitative, based on analyses of TCR repertoire and TCR signaling strength. However, these parameters are altered in the thymic Treg-precursor population, which is also markedly diminished in cRel-/- mice. Moreover, c-Rel governs the transcriptional programme of both thymic and peripheral Tregs, controlling a core of genes involved with immune signaling, and separately in the periphery, cell cycle progression. Last, the immune suppressive function of peripheral cRel-/- tTregs is diminished in a lymphopenic model of T cell proliferation and is associated with decreased stability of Foxp3 expression. Collectively, we show that c-Rel is a transcriptional regulator that controls multiple aspects of Treg development, differentiation, and function via distinct mechanisms.


Subject(s)
Proto-Oncogene Proteins c-rel/immunology , Proto-Oncogene Proteins c-rel/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Animals , Cell Differentiation/immunology , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Thymus Gland/immunology , Thymus Gland/metabolism
5.
Immunity ; 39(3): 573-83, 2013 Sep 19.
Article in English | MEDLINE | ID: mdl-24012421

ABSTRACT

Activation-induced cell death (AICD) plays a critical role in immune homeostasis and tolerance. In T-cell-dependent humoral responses, AICD of B cells is initiated by Fas ligand (FasL) on T cells, stimulating the Fas receptor on B cells. In contrast, T-cell-independent B cell responses involve innate-type B lymphocytes, such as marginal zone (MZ) B cells, and little is known about the mechanisms that control AICD during innate B cell responses to Toll-like receptor (TLR) activation. Here, we show that MZ B cells undergo AICD in response to TLR4 activation in vivo. The transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) receptor and TLR4 cooperate to upregulate expression of both FasL and Fas on MZ B cells and also to repress inhibitors of Fas-induced apoptosis signaling. These findings demonstrate an unappreciated role for TACI and its ligands in the regulation of AICD during T-cell-independent B cell responses.


Subject(s)
Apoptosis , Fas Ligand Protein/metabolism , Toll-Like Receptor 4/metabolism , Transmembrane Activator and CAML Interactor Protein/metabolism , fas Receptor/metabolism , Animals , B-Cell Activation Factor Receptor/biosynthesis , B-Lymphocytes/immunology , Enzyme Activation , Fas Ligand Protein/biosynthesis , Lipopolysaccharides , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Transmembrane Activator and CAML Interactor Protein/genetics
6.
J Immunol ; 202(5): 1479-1493, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30683700

ABSTRACT

Herpes simplex encephalitis (HSE), caused by HSV type 1 (HSV-1) infection, is an acute neuroinflammatory condition of the CNS and remains the most common type of sporadic viral encephalitis worldwide. Studies in humans have shown that susceptibility to HSE depends in part on the genetic make-up of the host, with deleterious mutations in the TLR3/type I IFN axis underlying some cases of childhood HSE. Using an in vivo chemical mutagenesis screen for HSV-1 susceptibility in mice, we identified a susceptible pedigree carrying a causal truncating mutation in the Rel gene (RelC307X ), encoding for the NF-κB transcription factor subunit c-Rel. Like Myd88-/- and Irf3-/- mice, RelC307X mice were susceptible to intranasal HSV-1 infection. Reciprocal bone marrow transfers into lethally irradiated hosts suggested that defects in both hematopoietic and CNS-resident cellular compartments contributed together to HSE susceptibility in RelC307X mice. Although the RelC307X mutation maintained cell-intrinsic antiviral control, it drove increased apoptotic cell death in infected fibroblasts. Moreover, reduced numbers of CD4+CD25+Foxp3+ T regulatory cells, and dysregulated NK cell and CD4+ effector T cell responses in infected RelC307X animals, indicated that protective immunity was also compromised in these mice. In the CNS, moribund RelC307X mice failed to control HSV-1 viral replication in the brainstem and cerebellum, triggering cell death and elevated expression of Ccl2, Il6, and Mmp8 characteristic of HSE neuroinflammation and pathology. In summary, our work implicates c-Rel in both CNS-resident cell survival and lymphocyte responses to HSV-1 infection and as a novel cause of HSE disease susceptibility in mice.


Subject(s)
Central Nervous System/immunology , Encephalitis, Herpes Simplex/immunology , Inflammation/immunology , Virus Replication/immunology , Animals , Chlorocebus aethiops , Encephalitis, Herpes Simplex/virology , Inflammation/virology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Vero Cells
7.
J Immunol ; 198(7): 2649-2660, 2017 04 01.
Article in English | MEDLINE | ID: mdl-28202617

ABSTRACT

Nucleotide-binding and oligomerization domain (NOD)-like receptors NOD1 and NOD2 are cytosolic innate immune receptors that recognize microbial peptidoglycans. Although studies have addressed the role of NOD proteins in innate immune responses, little attention has been given to their impact on the developing adaptive immune system. We have assessed the roles of NOD1 and NOD2 deficiency on T cell development in mice. Our results demonstrate that NOD1 and NOD2 promote the positive selection/maturation of CD8 single-positive thymocytes in a thymocyte-intrinsic manner. TCR-mediated ERK phosphorylation is significantly reduced in the absence of NOD proteins, but receptor-interacting protein 2 is not involved in CD8 single-positive thymocyte selection or ERK signaling. Commensal bacteria-free animals have thymocyte maturation defects, and exogenous NOD ligands can enhance thymocyte maturation in culture. These results raise the intriguing possibility that abnormal lymphocyte responses observed in NOD-dependent inflammatory diseases are not driven solely by microbial signals in the gut, but may also involve intrinsic lymphocyte defects resulting from impaired CD8 T cell thymic development.


Subject(s)
CD8-Positive T-Lymphocytes/cytology , Cell Differentiation/immunology , Nod1 Signaling Adaptor Protein/immunology , Nod2 Signaling Adaptor Protein/immunology , Thymocytes/cytology , Animals , CD8-Positive T-Lymphocytes/immunology , Immunoblotting , Mice , Mice, Inbred C57BL , Mice, Knockout , Polymerase Chain Reaction , Thymocytes/immunology , Thymus Gland/cytology , Thymus Gland/immunology
8.
Immunity ; 30(1): 56-66, 2009 Jan 16.
Article in English | MEDLINE | ID: mdl-19119023

ABSTRACT

Apoptotic death of hepatocytes, a contributor to many chronic and acute liver diseases, can be a consequence of overactivation of the immune system and is often mediated by TNFalpha. Injection with lipopolysaccharide (LPS) plus the transcriptional inhibitor D(+)-galactosamine (GalN) or mitogenic T cell activation causes fatal hepatocyte apoptosis in mice, which is mediated by TNFalpha, but the effector mechanisms remain unclear. Our analysis of gene-targeted mice showed that caspase-8 is essential for hepatocyte killing in both settings. Loss of Bid, the proapoptotic BH3-only protein activated by caspase-8 and essential for Fas ligand-induced hepatocyte killing, resulted only in a minor reduction of liver damage. However, combined loss of Bid and another BH3-only protein, Bim, activated by c-Jun N-terminal kinase (JNK), protected mice from LPS+GalN-induced hepatitis. These observations identify caspase-8 and the BH3-only proteins Bid and Bim as potential therapeutic targets for treatment of inflammatory liver diseases.


Subject(s)
Apoptosis Regulatory Proteins/metabolism , Apoptosis , BH3 Interacting Domain Death Agonist Protein/metabolism , Caspase 8/metabolism , Chemical and Drug Induced Liver Injury , Hepatocytes/pathology , Membrane Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Animals , Bcl-2-Like Protein 11 , Mice , Mice, Inbred C57BL , Mice, Knockout , Tumor Necrosis Factor-alpha/metabolism
9.
Proc Natl Acad Sci U S A ; 112(5): 1535-40, 2015 Feb 03.
Article in English | MEDLINE | ID: mdl-25605927

ABSTRACT

Inflammation is critical for host defense, but without appropriate control, it can cause chronic disease or even provoke fatal responses. Here we identify a mechanism that limits the inflammatory response. Probing the responses of macrophages to the key sensory Toll-like receptors, we identify that the Broad-complex, Tramtrack and Bric-a-brac/poxvirus and zinc finger (BTB/POZ), transcriptional regulator promyelocytic leukemia zinc finger (PLZF) limits the expression of inflammatory gene products. In accord with this finding, PLZF-deficient animals express higher levels of potent inflammatory cytokines and mount exaggerated inflammatory responses to infectious stimuli. Temporal quantitation of inflammatory gene transcripts shows increased gene induction in the absence of PLZF. Genome-wide analysis of histone modifications distinguish that PLZF establishes basal activity states of early response genes to maintain immune homeostasis and limit damaging inflammation. We show that PLZF stabilizes a corepressor complex that encompasses histone deacetylase activity to control chromatin. Together with our previous demonstration that PLZF promotes the antiviral response, these results suggest a strategy that could realize one of the major goals of immune therapy to retain immune resistance to pathogens while curbing damaging inflammation.


Subject(s)
Chromatin/metabolism , Inflammation/metabolism , Kruppel-Like Transcription Factors/metabolism , Signal Transduction , Animals , Bacterial Infections/metabolism , Chromatin Immunoprecipitation , Fluorescence Resonance Energy Transfer , Histone Deacetylases/metabolism , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Promyelocytic Leukemia Zinc Finger Protein , Real-Time Polymerase Chain Reaction
10.
EMBO J ; 31(3): 692-706, 2012 Feb 01.
Article in English | MEDLINE | ID: mdl-22124325

ABSTRACT

The role of specific members of the NF-κB family of transcription factors in CD8 T-cell selection and development is largely unknown. Here, we show that mice lacking NF-κB1 develop a unique population of conventional CD8 single-positive (SP) thymocytes with memory T cell-like properties that populate peripheral immune organs. Development of this memory-like population is not due to PLZF(+) thymocytes and instead coincides with changes in CD8 T-cell selection. These include a reduction in the efficiency of negative selection and a dependence on MHC class Ia or Ib expressed by haematopoietic cells. These findings indicate that NF-κB1 regulates multiple events in the thymus that collectively inhibit the excess development of CD8(+) thymocytes with memory cell characteristics.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/physiology , NF-kappa B/physiology , Thymus Gland/cytology , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Immunophenotyping , Interleukin-4/biosynthesis , NF-kappa B/genetics , Signal Transduction
11.
J Autoimmun ; 70: 52-62, 2016 06.
Article in English | MEDLINE | ID: mdl-27068879

ABSTRACT

The properties of CD4(+) regulatory T cell (Treg) subsets are dictated by distinct patterns of gene expression determined by FOXP3 and different combinations of various transcription factors. Here we show the NF-κB transcription factor RelA is constitutively active in naïve and effector Tregs. The conditional inactivation of Rela in murine FOXP3(+) cells induces a rapid onset, multi-focal autoimmune disease that depends on RelA being expressed in conventional T cells. In addition to promoting Treg lineage stability, RelA determines the size of the effector Treg population, a function influenced by the presence or absence of RelA in conventional T cells. These findings showing that RelA controls Treg stability and promotes the competitive fitness of effector Tregs highlight the importance of RelA activity in peripheral Treg induced tolerance.


Subject(s)
Immune Tolerance , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transcription Factor RelA/metabolism , Animals , Antibodies/blood , Antibodies/immunology , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Autoimmune Diseases/pathology , Autoimmunity , Biomarkers , Cluster Analysis , Cytokines/blood , Cytokines/metabolism , Disease Models, Animal , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Profiling , Immune Tolerance/genetics , Immunomodulation , Immunophenotyping , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Lymphocyte Count , Male , Mice , Mice, Transgenic , Phenotype , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Transcription Factor RelA/genetics
12.
J Pathol ; 236(3): 326-36, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25727407

ABSTRACT

NF-κB signalling is an important factor in the development of inflammation-associated cancers. Mouse models of Helicobacter-induced gastric cancer and colitis-associated colorectal cancer have demonstrated that classical NF-κB signalling is an important regulator of these processes. In the stomach, it has also been demonstrated that signalling involving specific NF-κB proteins, including NF-κB1/p50, NF-κB2/p52, and c-Rel, differentially regulate the development of gastric pre-neoplasia. To investigate the effect of NF-κB subunit loss on colitis-associated carcinogenesis, we administered azoxymethane followed by pulsed dextran sodium sulphate to C57BL/6, Nfkb1(-/-), Nfkb2(-/-), and c-Rel(-/-) mice. Animals lacking the c-Rel subunit were more susceptible to colitis-associated cancer than wild-type mice, developing 3.5 times more colonic polyps per animal than wild-type mice. Nfkb2(-/-) mice were resistant to colitis-associated cancer, developing fewer polyps per colon than wild-type mice (median 1 compared to 4). To investigate the mechanisms underlying these trends, azoxymethane and dextran sodium sulphate were administered separately to mice of each genotype. Nfkb2(-/-) mice developed fewer clinical signs of colitis and exhibited less severe colitis and an attenuated cytokine response compared with all other groups following DSS administration. Azoxymethane administration did not fully suppress colonic epithelial mitosis in c-Rel(-/-) mice and less colonic epithelial apoptosis was also observed in this genotype compared to wild-type counterparts. These observations demonstrate different functions of specific NF-κB subunits in this model of colitis-associated carcinogenesis. NF-κB2/p52 is necessary for the development of colitis, whilst c-Rel-mediated signalling regulates colonic epithelial cell turnover following DNA damage.


Subject(s)
Adenoma/metabolism , Colitis/complications , Colonic Neoplasms/metabolism , NF-kappa B p50 Subunit/metabolism , NF-kappa B p52 Subunit/metabolism , Proto-Oncogene Proteins c-rel/metabolism , Adenoma/chemically induced , Adenoma/etiology , Animals , Azoxymethane/toxicity , Cell Transformation, Neoplastic/metabolism , Colitis/chemically induced , Colonic Neoplasms/chemically induced , Colonic Neoplasms/etiology , Cytokines/metabolism , Dextran Sulfate/toxicity , Disease Models, Animal , Disease Susceptibility , Epithelial Cells/metabolism , Female , Inflammation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction
13.
Immunol Rev ; 246(1): 272-85, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22435561

ABSTRACT

Although the diverse functions served by the nuclear factor-κB (NF-κB) pathway in virtually all cell types are typically employed to deal with stress responses, NF-κB transcription factors also play key roles in the development of hemopoietic cells. This review focuses on how NF-κB transcription factors control various aspects of thymic T-cell and myeloid cell differentiation that include its roles in hemopoietic precursors, conventional αß T cells, CD4(+) regulatory T cells, natural killer T cells, γδ T cells, macrophages, and dendritic cells.


Subject(s)
Hematopoiesis/physiology , NF-kappa B/chemistry , NF-kappa B/metabolism , Protein Subunits/metabolism , Animals , Cell Lineage , Humans , Myeloid Cells/metabolism , T-Lymphocytes/metabolism , Thymocytes/metabolism
14.
J Biol Chem ; 289(46): 31693-31707, 2014 Nov 14.
Article in English | MEDLINE | ID: mdl-25266721

ABSTRACT

The polycomb group protein Ezh2 is a histone methyltransferase that modifies chromatin structure to alter gene expression during embryonic development, lymphocyte activation, and tumorigenesis. The mechanism by which Ezh2 expression is regulated is not well defined. In the current study, we report that c-Rel is a critical activator of Ezh2 transcription in lymphoid cells. In activated primary murine B and T cells, plus human leukemia and multiple myeloma cell lines, recruitment of c-Rel to the first intron of the Ezh2 locus promoted Ezh2 mRNA expression. This up-regulation was abolished in activated c-Rel-deficient lymphocytes and by c-Rel knockdown in Jurkat T cells. Treatment of malignant cells with the c-Rel inhibitor pentoxifylline not only reduced c-Rel nuclear translocation and Ezh2 expression, but also enhanced their sensitivity to the Ezh2-specific drug, GSK126 through increased growth inhibition and cell death. In summary, our demonstration that c-Rel regulates Ezh2 expression in lymphocytes and malignant lymphoid cells reveals a novel transcriptional network in transformed lymphoid cells expressing high levels of Ezh2 that provides a molecular justification for combinatorial drug therapy.


Subject(s)
Gene Expression Regulation, Neoplastic , Polycomb Repressive Complex 2/metabolism , Proto-Oncogene Proteins c-rel/metabolism , Animals , Base Sequence , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Survival , Enhancer of Zeste Homolog 2 Protein , HEK293 Cells , Humans , Indoles/chemistry , Jurkat Cells , Lymphocyte Activation , Lymphocytes/cytology , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Neoplasms/metabolism , Pentoxifylline/chemistry , Pyridones/chemistry , Transcription, Genetic , Up-Regulation
15.
EMBO Rep ; 14(11): 992-8, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24060902

ABSTRACT

The BH3-only protein Bim is a critical initiator of apoptosis in hematopoietic cells. Bim is upregulated in response to growth factor withdrawal and in vitro studies have implicated the transcription factor Foxo3a as a critical inducer. To test the importance of this regulation in vivo, we generated mice with mutated Foxo-binding sites within the Bim promoters (Bim(ΔFoxo/ΔFoxo)). Contrary to Bim-deficient mice, Bim(ΔFoxo/ΔFoxo) mice had a normal hematopoietic system. Moreover, cytokine-dependent haematopoietic cells from Bim(ΔFoxo/ΔFoxo) and wt mice died at similar rates. These results indicate that regulation of Bim by Foxo transcription factors is not critical for the killing of hematopoietic cells.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Apoptosis , Forkhead Transcription Factors/metabolism , Hematopoietic System/cytology , Membrane Proteins/genetics , Proto-Oncogene Proteins/genetics , Transcription, Genetic , Animals , Apoptosis/drug effects , Apoptosis/genetics , Apoptosis Regulatory Proteins/deficiency , Apoptosis Regulatory Proteins/metabolism , Base Sequence , Bcl-2-Like Protein 11 , Binding Sites , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Death/drug effects , Cytokines/pharmacology , Forkhead Box Protein O3 , Forkhead Transcription Factors/deficiency , HEK293 Cells , Hematopoiesis/drug effects , Hematopoietic System/drug effects , Hematopoietic System/metabolism , Humans , Lymphoma/pathology , Membrane Proteins/deficiency , Membrane Proteins/metabolism , Mice , Molecular Sequence Data , Mutation/genetics , Promoter Regions, Genetic/genetics , Protein Binding/drug effects , Protein Binding/genetics , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Thymocytes/cytology , Thymocytes/drug effects , Thymocytes/metabolism , Transcription, Genetic/drug effects
16.
J Immunol ; 187(9): 4483-91, 2011 Nov 01.
Article in English | MEDLINE | ID: mdl-21940679

ABSTRACT

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease involving effector Th subsets such as Th1 and Th17. In this study, we demonstrate that mice lacking the NF-κB transcription factor family member c-Rel (rel(-/-)), which are known to be resistant to EAE, show impaired Th17 development. Mixed bone marrow chimeras and EAE adoptive transfer experiments show that the deficiency of effector Th17 cells in rel(-/-) mice is T cell intrinsic. Consistent with this finding, c-Rel was activated in response to TCR signaling in the early stages of Th17 development and controlled the expression of Rorc, which encodes the Th17 transcription factor retinoic acid-related orphan receptor γt. CD28, but not IL-2, repression of Th17 development was dependent on c-Rel, implicating a dual role for c-Rel in modulating Th17 development. Adoptive transfer experiments also suggested that c-Rel control of regulatory T cell differentiation and homeostasis influences EAE development and severity by influencing the balance between Th17 and regulatory T cells. Collectively, our findings indicate that in addition to promoting Th1 differentiation, c-Rel regulates the development and severity of EAE via multiple mechanisms that impact on the generation of Th17 cells.


Subject(s)
Cell Differentiation/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Proto-Oncogene Proteins c-rel/physiology , Th17 Cells/cytology , Th17 Cells/immunology , Amino Acid Sequence , Animals , CD28 Antigens/physiology , Cell Differentiation/genetics , Cells, Cultured , Disease Resistance/genetics , Disease Resistance/immunology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Growth Inhibitors/deficiency , Growth Inhibitors/genetics , Growth Inhibitors/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Proto-Oncogene Proteins c-rel/deficiency , Proto-Oncogene Proteins c-rel/genetics , Severity of Illness Index , Th17 Cells/pathology
17.
J Immunol ; 186(9): 5468-77, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21421852

ABSTRACT

Rel/NF-κB transcription factors regulate inflammatory and immune responses. Despite possible subunit redundancy, NF-κB1-deficient (Nfkb1(-/-)) mice were profoundly protected from sterile CD4 T cell-dependent acute inflammatory arthritis and peritonitis. We evaluated CD4 T cell function in Nfkb1(-/-) mice and found increased apoptosis and selectively reduced GM-CSF production. Apoptosis was blocked by expression of a Bcl-2 transgene without restoring a disease response. In contrast with wild-type cells, transfer of Nfkb1(-/-) or GM-CSF-deficient CD4 T cells into RAG-1-deficient (Rag1(-/-)) mice failed to support arthritis induction. Injection of GM-CSF into Nfkb1(-/-) mice fully restored the disease response, suggesting that T cells are an important source of GM-CSF during acute inflammation. In Ag-induced peritonitis, NF-κB1-dependent GM-CSF production in CD4 T cells was required for disease and for generation of inflammatory monocyte-derived dendritic cells (MoDC), but not conventional dendritic cells. MoDC were identified in inflamed synovium and draining lymph nodes during arthritis. These MoDC produced high levels of MCP-1, a potent chemoattractant for monocytes. This study revealed two important findings: NF-κB1 serves a critical role in the production of GM-CSF by activated CD4 T cells during inflammatory responses, and GM-CSF derived from these cells drives the generation of MoDC during inflammatory disease.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Dendritic Cells/cytology , Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis , NF-kappa B p50 Subunit/immunology , Animals , Apoptosis/immunology , Arthritis, Experimental/immunology , Arthritis, Experimental/metabolism , Blotting, Western , CD4-Positive T-Lymphocytes/metabolism , Cell Separation , Dendritic Cells/immunology , Electrophoretic Mobility Shift Assay , Flow Cytometry , Inflammation/immunology , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B p50 Subunit/metabolism
18.
J Immunol ; 187(8): 4018-30, 2011 Oct 15.
Article in English | MEDLINE | ID: mdl-21900177

ABSTRACT

Costimulation-deficient dendritic cells (DCs) prevent autoimmune disease in mouse models. However, autoimmune-prone mice and humans fail to control expansion of peripheral autoreactive effector memory T cells (T(EMs)), which resist immunoregulation by costimulation-deficient DCs. In contrast, activation of DC costimulation may be coupled with regulatory capacity. To test whether costimulatory DCs control T(EMs) and attenuate established autoimmune disease, we used RelB-deficient mice, which have multiorgan inflammation, expanded peripheral autoreactive T(EMs), and dysfunctional Foxp3(+) regulatory T cells (Tregs) cells and conventional DCs. T(EMs) were regulated by Foxp3(+) Tregs when costimulated by CD3/CD28-coated beads or wild-type DCs but not DCs deficient in RelB or CD80/CD86. After transfer, RelB and CD80/CD86-sufficient DCs restored tolerance and achieved a long-term cure of autoimmune disease through costimulation of T(EM) and Foxp3(+) Treg IFN-γ production, as well as induction of IDO by host APCs. IDO was required for regulation of T(EMs) and suppression of organ inflammation. Our data challenge the paradigm that costimulation-deficient DCs are required to regulate established autoimmune disease to avoid T(EM) activation and demonstrate cooperative cross-talk between costimulatory DCs, IFN-γ, and IDO-dependent immune regulation. IFN-γ and IDO activity may be good surrogate biomarkers measured against clinical efficacy in trials of autoimmune disease immunoregulation.


Subject(s)
Autoimmune Diseases/immunology , Dendritic Cells/immunology , Immunotherapy/methods , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Animals , Autoimmune Diseases/therapy , Dendritic Cells/transplantation , Flow Cytometry , Immune Tolerance/immunology , Immunomagnetic Separation , Inflammation/immunology , Inflammation/therapy , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Signal Transduction/immunology , Transcription Factor RelB/deficiency , Transcription Factor RelB/genetics , Transcription Factor RelB/immunology
19.
Infect Immun ; 79(5): 1848-54, 2011 May.
Article in English | MEDLINE | ID: mdl-21343350

ABSTRACT

NF-κB is a critical regulator of gene expression during severe infections. NF-κB comprises homo- and heterodimers of proteins from the Rel family. Among them, p50 and p65 have been clearly implicated in the pathophysiology of sepsis. In contrast, the role of cRel in sepsis is still controversial and has been poorly studied in single-pathogen infections. We aimed to investigate the consequences of cRel deficiency in a cecal ligation and puncture (CLP) model of sepsis. We have approached the underlying mechanisms of host defense by analyzing bacterial clearance, systemic inflammation, and the distribution of spleen dendritic cell subsets. Moreover, by using a genome-wide technology, we have also analyzed the CLP-induced modifications in gene expression profiles both in wild-type (wt) and in rel(-/-) mice. The absence of cRel enhances mortality due to polymicrobial sepsis. Despite normal pathogen clearance, cRel deficiency leads to an altered systemic inflammatory response associated with a sustained loss of the spleen lymphoid dendritic cells. Furthermore, a whole-blood microarray study reveals that the differential outcome between wt and rel(-/-) mice during sepsis is preceded by remarkable changes in the expression of hundreds of genes involved in aspects of host-pathogen interaction, such as host survival and lipid metabolism. In conclusion, cRel is a key NF-κB member required for host antimicrobial defenses and a regulatory transcription subunit that controls the inflammatory and immune responses in severe infection.


Subject(s)
Host-Parasite Interactions/genetics , NF-kappa B/genetics , Proto-Oncogene Proteins c-rel/genetics , Sepsis/genetics , Animals , Blotting, Western , Disease Models, Animal , Electrophoretic Mobility Shift Assay , Female , Gene Expression , Gene Expression Profiling , Host-Parasite Interactions/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/immunology , NF-kappa B/metabolism , Oligonucleotide Array Sequence Analysis , Proto-Oncogene Proteins c-rel/immunology , Proto-Oncogene Proteins c-rel/metabolism , Sepsis/immunology , Sepsis/metabolism , Transcription Factor RelA/genetics , Transcription Factor RelA/immunology , Transcription Factor RelA/metabolism
20.
Eur J Immunol ; 40(3): 867-77, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19950170

ABSTRACT

Elucidating the signaling events that promote T-cell tolerance versus activation provides important insights for manipulating immunity in vivo. Previous studies have suggested that the absence of PKCtheta results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-kappaB plays a key role in determining whether T-cell anergy or activation is induced. Here, we examine whether Bcl-10 and specific family members of NF-kappaB act downstream of PKCtheta to alter CD8(+) T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-kappaB1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKCtheta-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKCtheta-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-kappaB, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKCtheta in controlling CD8(+) T-cell anergy induction.


Subject(s)
Adaptor Proteins, Signal Transducing/immunology , CD8-Positive T-Lymphocytes/immunology , Clonal Anergy/immunology , Isoenzymes/immunology , Lymphocyte Activation/immunology , Protein Kinase C/immunology , Proto-Oncogene Proteins c-rel/immunology , Animals , B-Cell CLL-Lymphoma 10 Protein , Blotting, Western , Mice , Mice, Transgenic , NF-kappa B/immunology , Phenotype , Protein Kinase C-theta , Signal Transduction/immunology
SELECTION OF CITATIONS
SEARCH DETAIL