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1.
Nat Immunol ; 20(4): 471-481, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30778241

RESUMEN

Foxp3+ regulatory T cells (Treg cells) are crucial for the maintenance of immune homeostasis both in lymphoid tissues and in non-lymphoid tissues. Here we demonstrate that the ability of intestinal Treg cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (TH17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal Treg cell populations, including RORγt+ Treg cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled Treg cell-derived IL-10 production and prevented excessive signaling via the kinases PI(3)K (phosphatidylinositol-3-OH kinase) and Akt and the metabolic checkpoint kinase complex mTORC1 (mammalian target of rapamycin) and expression of inflammatory cytokines in intestinal Treg cells. c-Maf deficiency in Treg cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal TH17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal Treg cells, which is essential for the establishment of host-microbe symbiosis.


Asunto(s)
Inmunoglobulina A/biosíntesis , Intestinos/inmunología , Microbiota , Proteínas Proto-Oncogénicas c-maf/fisiología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Células Cultivadas , Colitis/inmunología , Citocinas/metabolismo , Disbiosis , Regulación de la Expresión Génica , Homeostasis , Interleucina-10/biosíntesis , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-maf/genética , Proteínas Proto-Oncogénicas c-maf/metabolismo , Linfocitos T Reguladores/enzimología
3.
Nat Immunol ; 19(6): 538-546, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29777219

RESUMEN

Immune responses in tissues are constrained by the physiological properties of the tissue involved. Tissue-resident memory T cells (TRM cells) are a recently discovered lineage of T cells specialized for life and function within tissues. Emerging evidence has shown that TRM cells have a special role in the control of solid tumors. A high frequency of TRM cells in tumors correlates with favorable disease progression in patients with cancer, and studies of mice have shown that TRM cells are necessary for optimal immunological control of solid tumors. Here we describe what defines TRM cells as a separate lineage and how these cells are generated. Furthermore, we discuss the properties that allow TRM cells to operate in normal and transformed tissues, as well as implications for the treatment of patients with cancer.


Asunto(s)
Memoria Inmunológica/inmunología , Neoplasias/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Humanos , Ratones
4.
Cell ; 158(3): 506-21, 2014 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-25083866

RESUMEN

Adaptation of the endoplasmic reticulum (ER) pathway for MHC class I (MHC-I) presentation in dendritic cells enables cross-presentation of peptides derived from phagocytosed microbes, infected cells, or tumor cells to CD8 T cells. How these peptides intersect with MHC-I molecules remains poorly understood. Here, we show that MHC-I selectively accumulate within phagosomes carrying microbial components, which engage Toll-like receptor (TLR) signaling. Although cross-presentation requires Sec22b-mediated phagosomal recruitment of the peptide loading complex from the ER-Golgi intermediate compartment (ERGIC), this step is independent of TLR signaling and does not deliver MHC-I. Instead, MHC-I are recruited from an endosomal recycling compartment (ERC), which is marked by Rab11a, VAMP3/cellubrevin, and VAMP8/endobrevin and holds large reserves of MHC-I. While Rab11a activity stocks ERC stores with MHC-I, MyD88-dependent TLR signals drive IκB-kinase (IKK)2-mediated phosphorylation of phagosome-associated SNAP23. Phospho-SNAP23 stabilizes SNARE complexes orchestrating ERC-phagosome fusion, enrichment of phagosomes with ERC-derived MHC-I, and subsequent cross-presentation during infection.


Asunto(s)
Presentación de Antígeno , Endosomas/metabolismo , Fagosomas/metabolismo , Receptores Toll-Like/metabolismo , Animales , Células Dendríticas/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Tejido Linfoide , Ratones , Ovalbúmina/inmunología , Fagocitosis , Fosforilación , Transporte de Proteínas , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , Receptores Toll-Like/inmunología , Proteínas de Unión al GTP rab/metabolismo
5.
EMBO J ; 43(8): 1445-1483, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38499786

RESUMEN

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.


Asunto(s)
Apoferritinas , Linfocitos T Reguladores , Animales , Humanos , Ratones , Apoferritinas/genética , Apoferritinas/metabolismo , Linaje de la Célula/genética , Citosina/metabolismo , Factores de Transcripción Forkhead , Hierro/metabolismo
6.
Nat Immunol ; 17(12): 1467-1478, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27776108

RESUMEN

Tissue-resident memory T cells (TRM cells) in the airways mediate protection against respiratory infection. We characterized TRM cells expressing integrin αE (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung TRM cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint. A distinct set of transcription factors was active in CD103+ TRM cells, including Notch. Genetic and pharmacological experiments with mice revealed that Notch activity was required for the maintenance of CD103+ TRM cells. We have thus identified specialized programs underlying the residence, persistence, vigilance and tight control of human lung TRM cells.


Asunto(s)
Linfocitos T CD8-positivos/fisiología , Memoria Inmunológica , Subtipo H3N2 del Virus de la Influenza A/inmunología , Pulmón/inmunología , Infecciones por Orthomyxoviridae/inmunología , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Infecciones del Sistema Respiratorio/inmunología , Animales , Antígenos CD/metabolismo , Células Cultivadas , Femenino , Humanos , Cadenas alfa de Integrinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Receptor Notch1/genética , Receptor Notch2/genética
7.
Immunity ; 48(5): 1046-1059.e6, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29752063

RESUMEN

To obtain a molecular definition of regulatory T (Treg) cell identity, we performed proteomics and transcriptomics on various populations of human regulatory and conventional CD4+ T (Tconv) cells. A protein expression signature was identified that defines all Treg cells, and another signature that defines effector Treg cells. These signatures could not be extrapolated from transcriptome data. Unique cell-biological and metabolic features in Treg cells were defined, as well as specific adaptations in cytokine, TCR, and costimulatory receptor signaling pathways. One such adaptation-selective STAT4 deficiency-prevented destabilization of Treg cell identity and function by inflammatory cytokines, while these signals could still induce critical transcription factors and homing receptors via other pathways. Furthermore, our study revealed surface markers that identify FOXP3+CD4+ T cells with distinct functional properties. Our findings suggest that adaptation in signaling pathways protect Treg cell identity and present a resource for further research into Treg cell biology.


Asunto(s)
Adaptación Fisiológica , Proteómica/métodos , Transducción de Señal , Linfocitos T Reguladores/metabolismo , Western Blotting , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Células HEK293 , Humanos , Espectrometría de Masas , Receptores de Antígenos de Linfocitos T/metabolismo
8.
Nat Immunol ; 15(12): 1143-51, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25344724

RESUMEN

Activated CD8(+) T cells choose between terminal effector cell (TEC) or memory precursor cell (MPC) fates. We found that the signaling receptor Notch controls this 'choice'. Notch promoted the differentiation of immediately protective TECs and was correspondingly required for the clearance of acute infection with influenza virus. Notch activated a major portion of the TEC-specific gene-expression program and suppressed the MPC-specific program. Expression of Notch was induced on naive CD8(+) T cells by inflammatory mediators and interleukin 2 (IL-2) via pathways dependent on the metabolic checkpoint kinase mTOR and the transcription factor T-bet. These pathways were subsequently amplified downstream of Notch, creating a positive feedback loop. Notch thus functions as a central hub where information from different sources converges to match effector T cell differentiation to the demands of an infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Receptores Notch/inmunología , Subgrupos de Linfocitos T/inmunología , Inmunidad Adaptativa/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/citología , Separación Celular , Citometría de Flujo , Virus de la Influenza A , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Infecciones por Orthomyxoviridae/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Subgrupos de Linfocitos T/citología , Transcriptoma , Transducción Genética
9.
Nat Immunol ; 18(8): 870-872, 2017 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-28722713
11.
Immunity ; 43(5): 831-3, 2015 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-26588772

RESUMEN

The Notch pathway is an attractive therapeutic target for treatment of cancer and T cell-mediated pathology, but Notch inhibition leads to many side effects. Pinnell et al. (2015) demonstrate that oncogenic functions can be separated biochemically from other functions of Notch, opening new options for more selective targeting of this pathway.


Asunto(s)
Leucemia/metabolismo , Proteínas Inhibidoras de STAT Activados/metabolismo , Receptor Notch1/metabolismo , Linfocitos T/metabolismo , Factores de Transcripción/metabolismo , Animales , Humanos
12.
J Immunol ; 208(2): 384-395, 2022 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-34937744

RESUMEN

CD4+CD25+FOXP3+ regulatory T (Treg) cells control immunological tolerance. Treg cells are generated in the thymus (tTreg) or in the periphery. Their superior lineage fidelity makes tTregs the preferred cell type for adoptive cell therapy (ACT). How human tTreg cells develop is incompletely understood. By combining single-cell transcriptomics and flow cytometry, we in this study delineated three major Treg developmental stages in the human thymus. At the first stage, which we propose to name pre-Treg I, cells still express lineage-inappropriate genes and exhibit signs of TCR signaling, presumably reflecting recognition of self-antigen. The subsequent pre-Treg II stage is marked by the sharp appearance of transcription factor FOXO1 and features induction of KLF2 and CCR7, in apparent preparation for thymic exit. The pre-Treg II stage can further be refined based on the sequential acquisition of surface markers CD31 and GPA33. The expression of CD45RA, finally, completes the phenotype also found on mature recent thymic emigrant Treg cells. Remarkably, the thymus contains a substantial fraction of recirculating mature effector Treg cells, distinguishable by expression of inflammatory chemokine receptors and absence of CCR7. The developmental origin of these cells is unclear and warrants caution when using thymic tissue as a source of stable cells for ACT. We show that cells in the major developmental stages can be distinguished using the surface markers CD1a, CD27, CCR7, and CD39, allowing for their viable isolation. These insights help identify fully mature tTreg cells for ACT and can serve as a basis for further mechanistic studies into tTreg development.


Asunto(s)
Diferenciación Celular/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Timocitos/citología , Timo/citología , Células Cultivadas , Preescolar , Proteína Forkhead Box O1/metabolismo , Humanos , Tolerancia Inmunológica/inmunología , Factores de Transcripción de Tipo Kruppel/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Glicoproteínas de Membrana/metabolismo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , RNA-Seq/métodos , Receptores CCR7/metabolismo , Análisis de la Célula Individual , Timo/inmunología , Transcriptoma/genética , Secuenciación del Exoma
13.
Eur J Immunol ; 52(11): 1819-1828, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36189878

RESUMEN

Anti-viral T-cell responses are usually directed against a limited set of antigens, but often contain many T cells expressing different T-cell receptors (TCRs). Identical TCRs found within virus-specific T-cell populations in different individuals are known as public TCRs, but also TCRs highly-similar to these public TCRs, with only minor variations in amino acids on specific positions in the Complementary Determining Regions (CDRs), are frequently found. However, the degree of freedom at these positions was not clear. In this study, we used the HLA-A*02:01-restricted EBV-LMP2FLY -specific public TCR as model and modified the highly-variable position 5 of the CDR3ß sequence with all 20 amino acids. Our results demonstrate that amino acids at this particular position in the CDR3ß region of this TCR are completely inter-changeable, without loss of TCR function. We show that the inability to find certain variants in individuals is explained by their lower recombination probability rather than by steric hindrance.


Asunto(s)
Aminoácidos , Receptores de Antígenos de Linfocitos T , Linfocitos T , Péptidos/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta
14.
J Infect Dis ; 226(5): 833-842, 2022 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-32808978

RESUMEN

BACKGROUND: Adoptive transfer of genetically engineered T cells expressing antigen-specific T-cell receptors (TCRs) is an appealing therapeutic approach for Epstein-Barr virus (EBV)-associated malignancies of latency type II/III that express EBV antigens (LMP1/2). Patients who are HLA-A*01:01 positive could benefit from such products, since no T cells recognizing any EBV-derived peptide in this common HLA allele have been found thus far. METHODS: HLA-A*01:01-restricted EBV-LMP2-specific T cells were isolated using peptide major histocompatibility complex (pMHC) tetramers. Functionality was assessed by production of interferon gamma (IFN-γ) and cytotoxicity when stimulated with EBV-LMP2-expressing cell lines. Functionality of primary T cells transduced with HLA-A*01:01-restricted EBV-LMP2-specific TCRs was optimized by knocking out the endogenous TCRs of primary T cells (∆TCR) using CRISPR-Cas9 technology. RESULTS: EBV-LMP2-specific T cells were successfully isolated and their TCRs were characterized. TCR gene transfer in primary T cells resulted in specific pMHC tetramer binding and reactivity against EBV-LMP2-expressing cell lines. The mean fluorescence intensity of pMHC-tetramer binding was increased 1.5-2 fold when the endogenous TCRs of CD8+ T cells was knocked out. CD8+/∆TCR T cells modified to express EBV-LMP2-specific TCRs showed IFN-γ secretion and cytotoxicity toward EBV-LMP2-expressing malignant cell lines. CONCLUSIONS: We isolated the first functional HLA-A*01:01-restricted EBV-LMP2-specific T-cell populations and TCRs, which can potentially be used in future TCR gene therapy to treat EBV-associated latency type II/III malignancies.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Antígenos HLA-A , Herpesvirus Humano 4 , Receptores de Antígenos de Linfocitos T , Proteínas de la Matriz Viral , Humanos , Interferón gamma , Receptores de Antígenos de Linfocitos T/genética , Proteínas de la Matriz Viral/inmunología
15.
Eur J Immunol ; 51(6): 1377-1389, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33728639

RESUMEN

The Ig superfamily protein glycoprotein A33 (GPA33) has been implicated in immune dysregulation, but little is known about its expression in the immune compartment. Here, we comprehensively determined GPA33 expression patterns on human blood leukocyte subsets, using mass and flow cytometry. We found that GPA33 was expressed on fractions of B, dendritic, natural killer and innate lymphoid cells. Most prominent expression was found in the CD4+ T cell compartment. Naïve and CXCR5+ regulatory T cells were GPA33high , and naïve conventional CD4+ T cells expressed intermediate GPA33 levels. The expression pattern of GPA33 identified functional heterogeneity within the CD4+ central memory T cell (Tcm) population. GPA33+ CD4+ Tcm cells were fully undifferentiated, bona fide Tcm cells that lack immediate effector function, whereas GPA33- Tcm cells exhibited rapid effector functions and may represent an early stage of differentiation into effector/effector memory T cells before loss of CD62L. Expression of GPA33 in conventional CD4+ T cells suggests a role in localization and/or preservation of an undifferentiated state. These results form a basis to study the function of GPA33 and show it to be a useful marker to discriminate between different cellular subsets, especially in the CD4+ T cell lineage.


Asunto(s)
Biomarcadores/metabolismo , Linfocitos T CD4-Positivos/inmunología , Leucocitos Mononucleares/inmunología , Glicoproteínas de Membrana/metabolismo , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Diferenciación Celular , Linaje de la Célula , Separación Celular , Citometría de Flujo , Células HEK293 , Humanos , Inmunidad Innata , Memoria Inmunológica , Glicoproteínas de Membrana/genética , Receptores CXCR5/metabolismo
16.
J Immunol ; 204(12): 3139-3148, 2020 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-32366581

RESUMEN

FOXP3-expressing regulatory T (Treg) cells safeguard immunological tolerance. Treg cells can be generated during thymic development (called thymic Treg [tTreg] cells) or derived from mature conventional CD4+ T cells that underwent TGF-ß-mediated conversion in the periphery (called peripheral Treg [pTreg] cells). Murine studies have shown that tTreg cells exhibit strong lineage fidelity, whereas pTreg cells can revert into conventional CD4+ T cells. Their stronger lineage commitment makes tTreg cells the safest cells to use in adoptive cell therapy, increasingly used to treat autoimmune and inflammatory disorders. Markers to distinguish human tTreg cells from pTreg cells have, however, not been found. Based on combined proteomic and transcriptomic approaches, we report that the Ig superfamily protein GPA33 is expressed on a subset of human Treg cells. GPA33 is acquired late during tTreg cell development but is not expressed on TGF-ß-induced Treg cells. GPA33 identifies Treg cells in human blood that lack the ability to produce effector cytokines (IL-2, IFN-γ, IL-17), regardless of differentiation stage. GPA33high Treg cells universally express the transcription factor Helios that preferentially marks tTreg cells and can robustly and stably be expanded in vitro even without rapamycin. Expanded GPA33high Treg cells are suppressive, unable to produce proinflammatory cytokines, and exhibit the epigenetic modifications of the FOXP3 gene enhancer CNS2, necessary for indelible expression of this critical transcription factor. Our findings thus suggest that GPA33 identifies human tTreg cells and provide a strategy to isolate such cells for safer and more efficacious adoptive cell therapy.


Asunto(s)
Biomarcadores/metabolismo , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Cultivadas , Citocinas/metabolismo , Factores de Transcripción Forkhead/metabolismo , Humanos , Tolerancia Inmunológica/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Activación de Linfocitos/inmunología , Factor de Crecimiento Transformador beta/metabolismo
17.
J Allergy Clin Immunol ; 142(1): 76-85.e8, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29111218

RESUMEN

BACKGROUND: The Notch signaling pathway has been implicated in the pathogenesis of allergic airway inflammation. Targeting the active Notch transactivation complex by using the cell-permeable, hydrocarbon-stapled synthetic peptide stapled α-helical peptide derived from mastermind-like 1 (SAHM1) resulted in genome-wide suppression of Notch-activated genes in leukemic cells and other models. However, the efficacy of SAHM1 in allergic asthma models has remained unexplored. OBJECTIVE: We aimed to investigate the therapeutic efficacy of SAHM1 in a house dust mite (HDM)-driven asthma model. METHODS: Topical therapeutic intervention with SAHM1 or a control peptide was performed during sensitization, challenge, or both with HDM in mice. Airway inflammation was assessed by using multicolor flow cytometry, and bronchial hyperreactivity was studied. Additionally, SAHM1 therapy was investigated in mice with established allergic airway inflammation and in a model in which we neutralized IFN-γ during HDM challenge to support the TH2 response and exacerbate asthma. RESULTS: SAHM1 treatment during the challenge phase led to a marked reduction of eosinophil and T cell numbers in bronchoalveolar lavage fluid compared with those in diluent-treated or control peptide-treated mice. Likewise, T-cell cytokine content and bronchial hyperreactivity were reduced. SAHM1 treatment dampened TH2 inflammation during ongoing HDM challenge and enhanced recovery after established asthma. Additionally, in the presence of anti-IFN-γ antibodies, SAHM1 downregulated expression of the key TH2 transcription factor GATA3 and intracellular IL-4 in bronchoalveolar lavage fluid T cells, but expression of the TH17 transcription factor retinoic acid-related orphan receptor γt or intracellular IL-17 was not affected. SAHM1 therapy also reduced serum IgE levels. CONCLUSIONS: Therapeutic intervention of Notch signaling by SAHM1 inhibits allergic airway inflammation in mice and is therefore an interesting new topical treatment opportunity in asthmatic patients.


Asunto(s)
Asma/inmunología , Hipersensibilidad Inmediata/inmunología , Péptidos Cíclicos/farmacología , Receptores Notch/antagonistas & inhibidores , Animales , Hiperreactividad Bronquial/inmunología , Ratones , Ratones Endogámicos C57BL , Pyroglyphidae
18.
Trends Immunol ; 36(12): 802-814, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26617322

RESUMEN

Differentiation of naïve T cells into effector cells is required for optimal protection against different classes of microbial pathogen and for the development of immune memory. Recent findings have revealed important roles for the Notch signaling pathway in T cell differentiation into all known effector subsets, raising the question of how this pathway controls such diverse differentiation programs. Studies in preclinical models support the therapeutic potential of manipulating the Notch pathway to alleviate immune pathology, highlighting the importance of understanding the mechanisms through which Notch regulates T cell differentiation and function. We review these findings here, and outline both unifying principles involved in Notch-mediated T cell fate decisions and cell type- and context-specific differences that may present the most suitable points for therapeutic intervention.


Asunto(s)
Diferenciación Celular/inmunología , Receptores Notch/inmunología , Linfocitos T/inmunología , Animales , Humanos , Activación de Linfocitos/inmunología , Transducción de Señal/inmunología
19.
J Allergy Clin Immunol ; 140(4): 1079-1089, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28111308

RESUMEN

BACKGROUND: Allergic asthma is characterized by a TH2 response induced by dendritic cells (DCs) that present inhaled allergen. Although the mechanisms by which they instruct TH2 differentiation are still poorly understood, expression of the Notch ligand Jagged on DCs has been implicated in this process. OBJECTIVE: We sought to establish whether Notch signaling induced by DCs is critical for house dust mite (HDM)-driven allergic airway inflammation (AAI) in vivo. METHODS: The induction of Notch ligand expression on DC subsets by HDM was quantified by using quantitative real-time PCR. We used an HDM-driven asthma mouse model to compare the capacity of Jagged 1 and Jagged 2 single- and double-deficient DCs to induce AAI. In addition, we studied AAI in mice with a T cell-specific deletion of recombination signal-binding protein for immunoglobulin Jκ region (RBPJκ), a downstream effector of Notch signaling. RESULTS: HDM exposure promoted expression of Jagged 1, but not Jagged 2, on DCs. In agreement with published findings, in vitro-differentiated and HDM-pulsed Jagged 1 and Jagged 2 double-deficient DCs lacked the capacity to induce AAI. However, after in vivo intranasal sensitization and challenge with HDM, DC-specific Jagged 1 or Jagged 2 single- or double-deficient mice had eosinophilic airway inflammation and a TH2 cell activation phenotype that was not different from that in control littermates. In contrast, RBPJκ-deficient mice did not experience AAI and airway hyperreactivity. CONCLUSION: Our results show that the Notch signaling pathway in T cells is crucial for the induction of TH2-mediated AAI in an HDM-driven asthma model but that expression of Jagged 1 or Jagged 2 on DCs is not required.


Asunto(s)
Células Dendríticas/inmunología , Hipersensibilidad/inmunología , Proteína Jagged-1/metabolismo , Proteína Jagged-2/metabolismo , Receptores Notch/metabolismo , Células Th2/inmunología , Animales , Antígenos Dermatofagoides/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Humanos , Proteína Jagged-1/genética , Proteína Jagged-2/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pyroglyphidae/inmunología , Transducción de Señal
20.
Nature ; 474(7351): 385-9, 2011 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-21602824

RESUMEN

Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen-associated molecular patterns (PAMPs), which are detected by the immune system, are present in both live and killed vaccines, indicating that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the mammalian innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA as a vita-PAMP present only in viable bacteria, the recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even non-pathogenic bacteria in sterile tissues can trigger similar responses, provided that they are alive. Thus, the immune system actively gauges the infectious risk by searching PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers a state of alert not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines.


Asunto(s)
Inmunidad Innata/inmunología , Viabilidad Microbiana/genética , Viabilidad Microbiana/inmunología , ARN Bacteriano/inmunología , ARN Mensajero/inmunología , Proteínas Adaptadoras del Transporte Vesicular/deficiencia , Proteínas Adaptadoras del Transporte Vesicular/inmunología , Animales , Anticuerpos Antibacterianos/inmunología , Bacterias/genética , Bacterias/inmunología , Bacterias/patogenicidad , Vacunas Bacterianas/genética , Vacunas Bacterianas/inmunología , Proteínas Portadoras/metabolismo , Células Cultivadas , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/microbiología , Inflamasomas/inmunología , Inflamasomas/metabolismo , Interferón beta/genética , Interferón beta/inmunología , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Fagocitosis , Fagosomas/inmunología , Fagosomas/microbiología , ARN Bacteriano/genética , ARN Mensajero/genética , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología , Vacunas de Productos Inactivados/inmunología , Factores de Virulencia
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