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1.
PLoS Pathog ; 10(1): e1003900, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24453980

RESUMEN

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune reactions. While TREM-1-amplified responses likely aid an improved detection and elimination of pathogens, excessive production of cytokines and oxygen radicals can also severely harm the host. Studies addressing the pathogenic role of TREM-1 during endotoxin-induced shock or microbial sepsis have so far mostly relied on the administration of TREM-1 fusion proteins or peptides representing part of the extracellular domain of TREM-1. However, binding of these agents to the yet unidentified TREM-1 ligand could also impact signaling through alternative receptors. More importantly, controversial results have been obtained regarding the requirement of TREM-1 for microbial control. To unambiguously investigate the role of TREM-1 in homeostasis and disease, we have generated mice deficient in Trem1. Trem1(-/-) mice are viable, fertile and show no altered hematopoietic compartment. In CD4(+) T cell- and dextran sodium sulfate-induced models of colitis, Trem1(-/-) mice displayed significantly attenuated disease that was associated with reduced inflammatory infiltrates and diminished expression of pro-inflammatory cytokines. Trem1(-/-) mice also exhibited reduced neutrophilic infiltration and decreased lesion size upon infection with Leishmania major. Furthermore, reduced morbidity was observed for influenza virus-infected Trem1(-/-) mice. Importantly, while immune-associated pathologies were significantly reduced, Trem1(-/-) mice were equally capable of controlling infections with L. major, influenza virus, but also Legionella pneumophila as Trem1(+/+) controls. Our results not only demonstrate an unanticipated pathogenic impact of TREM-1 during a viral and parasitic infection, but also indicate that therapeutic blocking of TREM-1 in distinct inflammatory disorders holds considerable promise by blunting excessive inflammation while preserving the capacity for microbial control.


Asunto(s)
Colitis/inmunología , Virus de la Influenza A/inmunología , Legionella pneumophila/inmunología , Enfermedad de los Legionarios/inmunología , Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Glicoproteínas de Membrana/deficiencia , Infecciones por Orthomyxoviridae/inmunología , Receptores Inmunológicos/deficiencia , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Colitis/inducido químicamente , Colitis/genética , Colitis/patología , Colitis/terapia , Modelos Animales de Enfermedad , Enfermedad de los Legionarios/genética , Enfermedad de los Legionarios/patología , Enfermedad de los Legionarios/terapia , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/patología , Leishmaniasis Cutánea/terapia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Noqueados , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/terapia , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Receptor Activador Expresado en Células Mieloides 1
2.
Eur J Immunol ; 41(3): 773-9, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21341263

RESUMEN

Intestinal mononuclear phagocytes (iMNP) are critically involved in mucosal immunity and tissue homeostasis. Two major non-overlapping populations of iMNP have been identified in mice. CD103(+) iMNP represent a migratory population capable of inducing tolerogenic responses, whereas CX3CR1(+) iMNP are resident cells with disease-promoting potential. CX3CR1(+) iMNP can further be subdivided based on differential expression of CX3CR1. Using CX3CR1(GFP/+) ×RAG2(-/-) mice, we demonstrate that CX3CR1(hi) and CX3CR1(lo) iMNP clearly differ with respect to their morphological and functional properties. Compared with CX3CR1(hi) iMNP, CX3CR1(lo) iMNP are polarised towards pro-inflammatory responses already under homeostatic conditions. During a CD4(+) T-cell-induced colitis, CX3CR1(lo) cells accumulate in the inflamed mucosa and upregulate the expression of pro-inflammatory cytokines and triggering receptor expressed on myeloid cells-1 (TREM-1). In contrast, CX3CR1(hi) iMNP retain their non-inflammatory profile even during intestinal inflammation. These findings identify two functionally distinct iMNP subsets based on differential expression of CX3CR1 and indicate an unanticipated stability of iMNP.


Asunto(s)
Fagocitos/clasificación , Fagocitos/inmunología , Receptores de Quimiocina/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Receptor 1 de Quimiocinas CX3C , Colitis/inmunología , Colitis/patología , Citocinas/biosíntesis , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Perfilación de la Expresión Génica , Homeostasis , Inmunidad Mucosa , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Receptores de Quimiocina/genética , Receptores Inmunológicos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Receptor Activador Expresado en Células Mieloides 1
3.
Eur J Immunol ; 39(7): 1743-53, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19551899

RESUMEN

TNF plays fundamental roles in the induction and perpetuation of inflammation. The effects of TNF are mediated through TNF receptor (TNFR) 1 or 2. As these two receptors mediate different functions, selective targeting of one receptor may represent a more specific treatment for inflammatory disorders than the complete blocking of TNF. TNFR2 expression is up-regulated in inflammatory bowel disease. Hence, we directly assessed the role of TNFR2 signaling in the CD4(+) T-cell transfer model of colitis using TNFR2(-/-) or WT mice as donors of colitogenic CD4(+)CD45RB(hi) T cells for transfer into syngeneic RAG2(-/-) or RAG2(-/-)TNFR2(-/-) recipient mice. Although the absence of TNFR2 expression by non-lymphoid cells of the recipient mice does not influence the course of colitis, transfer of TNFR2(-/-) CD4(+) T cells leads to an accelerated onset of disease and to more severe signs of inflammation. The enhanced colitogenic potential of TNFR2(-/-) CD4(+) T cells is associated with reduced activation-induced cell death, resulting in an increased accumulation of TNFR2(-/-) CD4(+) T cells. Hence, TNFR2 signaling is crucial for the TNF-dependent contraction of the disease-inducing T cells. Therefore, a selective blocking of TNFR2 may lead to exacerbation rather than attenuation of T-cell-mediated inflammatory disorders.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Colitis/metabolismo , Proteínas de Unión al ADN/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Traslado Adoptivo/métodos , Animales , Apoptosis , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/trasplante , Diferenciación Celular , Proliferación Celular , Colitis/genética , Colitis/terapia , Colon/inmunología , Colon/metabolismo , Colon/patología , Proteínas de Unión al ADN/genética , Citometría de Flujo , Expresión Génica , Interferón gamma/genética , Interleucina-17/genética , Interleucina-4/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/genética
4.
Immunology ; 128(3): 351-9, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20067535

RESUMEN

Maintenance of intestinal epithelial barrier function is of vital importance in preventing uncontrolled influx of antigens and the potentially ensuing inflammatory disorders. Intestinal intraepithelial lymphocytes (IEL) are in intimate contact with epithelial cells and may critically regulate the epithelial barrier integrity. While a preserving impact has been ascribed to the T-cell receptor (TCR)-gammadelta subset of IEL, IEL have also been shown to attenuate the barrier function. The present study sought to clarify the effects of IEL by specifically investigating the influence of the TCR-alphabeta CD8alphabeta and TCR-alphabeta CD8alphaalpha subsets of IEL on the intestinal epithelial barrier integrity. To this end, an in vitro coculture system of the murine intestinal crypt-derived cell-line mIC(cl2) and syngeneic ex vivo isolated IEL was employed. Epithelial integrity was assessed by analysis of transepithelial resistance (TER) and paracellular flux of fluorescein isothiocyanate-conjugated (FITC-) dextran. The TCR-alphabeta CD8alphaalpha IEL and resting TCR-alphabeta CD8alphabeta IEL did not affect TER of mIC(cl2) or flux of FITC-dextran. In contrast, activated TCR-alphabeta CD8alphabeta IEL clearly disrupted the integrity of the mIC(cl2) monolayer. No disrupting effect was seen with activated TCR-alphabeta CD8alphabeta IEL from interferon-gamma knockout mice. These findings demonstrate that secretion of interferon-gamma by activated TCR-alphabeta CD8alphabeta IEL is strictly required and also sufficient for disrupting the intestinal epithelial barrier function.


Asunto(s)
Permeabilidad de la Membrana Celular , Mucosa Intestinal/fisiología , Linfocitos T/metabolismo , Animales , Antígenos CD8/biosíntesis , Línea Celular , Técnicas de Cocultivo , Dextranos/metabolismo , Impedancia Eléctrica , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Interferón gamma/genética , Activación de Linfocitos , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Linfocitos T/inmunología
5.
J Clin Invest ; 111(8): 1191-9, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12697738

RESUMEN

Death receptor-mediated activation-induced apoptosis of antigen-specific T cells is a major mechanism of peripheral tolerance induction and immune homeostasis. Failure to undergo activation-induced cell death (AICD) is an important underlying cause of many autoimmune diseases. Thus, enhancing the T cell's own suicide mechanism may provide an efficient therapy for the treatment of autoimmune diseases. Bisindolylmaleimide VIII (Bis VIII), a PKC inhibitor, can sensitize T cells for death receptor-induced apoptosis and thus can inhibit the development of T cell-mediated autoimmune disease in vivo. In this study, we have analyzed the functional consequences of accelerated suicide for a protective CD8+ T cell-mediated immune response. Our data indicate that CD8+ T cells are sensitized by Bis VIII to AICD, both in vitro and in vivo. The sensitizing effect of Bis VIII appears to be mediated by specific downmodulation of the antiapoptotic molecule cellular FLICE-like inhibitory protein (cFLIP(L)). Importantly, Bis VIII administration during an acute lymphocytic choriomeningitis virus (LCMV) infection causes the depletion of virus-specific CD8+ T cells and subsequently impaired cytotoxicity and virus clearance. We conclude that resistance to death receptor-induced apoptosis is crucial for the efficient induction of a protective immune response, and that Bis VIII-based immunotherapies have to be applied under well-controlled conditions to avoid the induction of immune incompetence and the inability to respond to pathogen infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Péptidos y Proteínas de Señalización Intracelular , Animales , Apoptosis/efectos de los fármacos , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Proteínas Portadoras/análisis , Citotoxicidad Inmunológica , Tolerancia Inmunológica , Inmunoterapia , Indoles/farmacología , Activación de Linfocitos , Maleimidas/farmacología , Ratones , Ratones Endogámicos C57BL , Replicación Viral/efectos de los fármacos
6.
Vet Immunol Immunopathol ; 120(3-4): 115-23, 2007 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17658618

RESUMEN

'B-cell activating factor belonging to the TNF family' (BAFF) represents a cytokine produced by antigen presenting cells promoting B-cell maturation, activation and immunoglobulin class switching. In the present study, we demonstrate expression of BAFF on cultured monocyte-derived dendritic cells, which is further enhanced by interferon-alpha or interferon-gamma treatment. From these cells, porcine BAFF was cloned and the recombinant protein was expressed in mammalian cells with and without a FLAG tag at the carboxyl terminus. Only the protein without the FLAG tag was bioactive in vitro, and promoted B-cell survival and the differentiation of foot-and-mouth disease virus (FMDV)-specific memory B cells into antibody producing cells. Based on this result it was tested whether BAFF can enhance FMDV antibody responses in the context of a DNA vaccination. To this end, pigs were immunised with the anti-FMDV DNA vaccine plasmid pcDNA3.1/P1-2A3C3D and a pCI plasmid expressing porcine BAFF. Using a needle-free transdermal application method, also referred to as 'jet injection', pigs were vaccinated three times and their humoral response quantified by ELISA and a virus neutralisation test. After the third vaccination, three out of six animals vaccinated with the pcDNA3.1/P1-2A3C3D alone but none of the animals that also received the BAFF expressing plasmid had seroconverted. These data suggest that BAFF is not appropriate as a genetic adjuvant when applied as a simple co-injection with the antigen-encoding plasmid.


Asunto(s)
Anticuerpos Antivirales/inmunología , Factor Activador de Células B/metabolismo , Virus de la Fiebre Aftosa/inmunología , Porcinos/inmunología , Vacunas de ADN/inmunología , Vacunas Virales/inmunología , Secuencia de Aminoácidos , Animales , Regulación de la Expresión Génica , Modelos Animales , Datos de Secuencia Molecular , Proteínas Recombinantes , Organismos Libres de Patógenos Específicos
7.
Sci Rep ; 7(1): 14870, 2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-29093489

RESUMEN

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses. Increasing evidence suggests a role for TREM-1 not only in acute pathogen-induced reactions but also in chronic and non-infectious inflammatory disorders, including various types of cancer. Here, we demonstrate that genetic deficiency in Trem1 protects from colorectal cancer. In particular, Trem1 -/- mice exhibited reduced tumor numbers and load in an experimental model of inflammation-driven tumorigenesis. Gene expression analysis of Trem1 -/- versus Trem1 +/+ tumor tissue demonstrated distinct immune signatures. Whereas Trem1 -/- tumors showed an increased abundance of transcripts linked to adaptive immunity, Trem1 +/+ tumors were characterized by overexpression of innate pro-inflammatory genes associated with tumorigenesis. Compared to adjacent tumor-free colonic mucosa, expression of Trem1 was increased in murine and human colorectal tumors. Unexpectedly, TREM-1 was not detected on tumor-associated Ly6C- MHC class II+ macrophages. In contrast, TREM-1 was highly expressed by tumor-infiltrating neutrophils which represented the predominant myeloid population in Trem1 +/+ but not in Trem1 -/- tumors. Collectively, our findings demonstrate a clear role of TREM-1 for intestinal tumorigenesis and indicate TREM-1-expressing neutrophils as critical players in colorectal tumor development.


Asunto(s)
Carcinogénesis/efectos de los fármacos , Neoplasias Intestinales/patología , Receptor Activador Expresado en Células Mieloides 1/fisiología , Animales , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Humanos , Inmunidad Innata , Inflamación , Neoplasias Intestinales/etiología , Neoplasias Intestinales/metabolismo , Ratones , Neutrófilos/metabolismo , Receptor Activador Expresado en Células Mieloides 1/deficiencia , Receptor Activador Expresado en Células Mieloides 1/genética
8.
Nat Commun ; 7: 13151, 2016 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-27762264

RESUMEN

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses, but its significance in non-infectious diseases remains unclear. Here, we demonstrate that TREM-1 promotes cardiovascular disease by exacerbating atherosclerosis. TREM-1 is expressed in advanced human atheromas and is highly upregulated under dyslipidemic conditions on circulating and on lesion-infiltrating myeloid cells in the Apoe-/- mouse model. TREM-1 strongly contributes to high-fat, high-cholesterol diet (HFCD)-induced monocytosis and synergizes with HFCD serum-derived factors to promote pro-inflammatory cytokine responses and foam cell formation of human monocyte/macrophages. Trem1-/-Apoe-/- mice exhibit substantially attenuated diet-induced atherogenesis. In particular, our results identify skewed monocyte differentiation and enhanced lipid accumulation as novel mechanisms through which TREM-1 can promote atherosclerosis. Collectively, our findings illustrate that dyslipidemia induces TREM-1 surface expression on myeloid cells and subsequently synergizes with TREM-1 to enhance monopoiesis, pro-atherogenic cytokine production and foam cell formation.


Asunto(s)
Aterosclerosis/genética , Dislipidemias/genética , Células Espumosas/inmunología , Metabolismo de los Lípidos/genética , Receptor Activador Expresado en Células Mieloides 1/genética , Animales , Antígenos Ly/genética , Antígenos Ly/inmunología , Aorta/inmunología , Aorta/patología , Apolipoproteínas E/genética , Apolipoproteínas E/inmunología , Aterosclerosis/etiología , Aterosclerosis/inmunología , Aterosclerosis/patología , Diferenciación Celular , Línea Celular , Colesterol/administración & dosificación , Citocinas/genética , Citocinas/inmunología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Dislipidemias/etiología , Dislipidemias/inmunología , Dislipidemias/patología , Femenino , Células Espumosas/patología , Regulación de la Expresión Génica , Humanos , Inflamación , Metabolismo de los Lípidos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Monocitos/patología , Receptor Activador Expresado en Células Mieloides 1/deficiencia , Receptor Activador Expresado en Células Mieloides 1/inmunología
9.
Ann N Y Acad Sci ; 1029: 180-92, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15681757

RESUMEN

Mucosal antigen delivery can induce tolerance, as shown by suppression of subsequent responses to antigen. Our previous work showed that both intranasal and oral routes of antigen delivery were effective but indicated that the intranasal route might be more reliable. Intranasal peptide administration induced cells that could mediate bystander suppression of responses to associated antigenic epitopes. Here, we discuss further investigation into the nature of intranasal, peptide-induced tolerance. Cells from mice treated with intranasal peptide became anergic and shut down secretion of cytokines such as IL-2, but still secreted IL-10. This latter cytokine was required for suppression of immune responses in vivo even though suppression of responses in vitro was IL-10 independent. Intranasal peptide induced a subset of CD25(-), CTLA-4(+) regulatory cells that suppressed naive cell function in vitro and in vivo. We provide evidence that these cells arise from CD25(-) precursors and differentiate independently from natural CD25(+) regulatory cells. IL-10-secreting regulatory cells are also found in the peripheral blood of humans and can be induced by soluble peptide administration. This route of tolerance induction offers promise as a means of antigen-specific immunotherapy of allergic and autoimmune conditions in humans.


Asunto(s)
Antígenos/inmunología , Inmunidad Mucosa , Subgrupos de Linfocitos T/inmunología , Administración Oral , Animales , Diseño de Fármacos , Humanos , Tolerancia Inmunológica/inmunología , Inflamación/inmunología , Ratones , Oligopéptidos/síntesis química , Oligopéptidos/inmunología , Células Th2
10.
J Crohns Colitis ; 6(9): 913-23, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22410349

RESUMEN

BACKGROUND & AIMS: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory responses. We have previously demonstrated a substantial increase in TREM-1-expressing macrophages in the inflamed intestinal mucosa of patients with inflammatory bowel diseases (IBD). TREM-1 is also produced as a soluble receptor (sTREM-1). Here, we aimed to determine whether serum sTREM-1 could be used as a surrogate marker of disease activity in patients with IBD. METHODS: Intestinal biopsies and concurrently collected sera from patients with Crohn's disease (CD) and Ulcerative colitis (UC) enrolled in the Swiss IBD cohort study were analyzed for intestinal TREM-1 mRNA and serum sTREM-1 expression. TREM-1 mRNA and sTREM-1 were correlated with the endoscopically determined disease activity. Serum sTREM-1 and TREM-1 mRNA expression levels were further determined in sera and colonic tissues collected at various time-points post disease induction in an experimental mouse model of colitis and correlated with disease activity. RESULTS: Expression of TREM-1 mRNA was upregulated in intestinal biopsies from patients with active disease but not in patients with quiescent disease. Serum sTREM-1 was elevated in IBD patients compared to normal controls. No substantial differences in sTREM-1 expression levels were found in patients with active versus quiescent disease. In colitic mice, colonic TREM-1 mRNA and serum sTREM-1 were also upregulated. While colonic TREM-1 mRNA expression levels correlated with disease activity, augmented serum sTREM-1 in fact associated with a milder course of disease. CONCLUSIONS: Analysis of sTREM-1 as a surrogate marker of disease activity in patients with IBD warrants caution.


Asunto(s)
Colitis Ulcerosa/sangre , Enfermedad de Crohn/sangre , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/genética , ARN Mensajero/sangre , Receptores Inmunológicos/sangre , Receptores Inmunológicos/genética , Traslado Adoptivo , Adulto , Animales , Área Bajo la Curva , Biomarcadores/sangre , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Colon/patología , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Endoscopía Gastrointestinal , Femenino , Humanos , Íleon/patología , Masculino , Ratones , Persona de Mediana Edad , ARN Mensajero/metabolismo , Curva ROC , Estadísticas no Paramétricas , Receptor Activador Expresado en Células Mieloides 1
11.
Semin Immunopathol ; 31(2): 171-84, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19533135

RESUMEN

Intestinal macrophages, preferentially located in the subepithelial lamina propria, represent the largest pool of tissue macrophages in humans. As an adaptation to the local antigen- and bacteria-rich environment, intestinal macrophages exhibit several distinct phenotypic and functional characteristics. Notably, microbe-associated molecular pattern receptors, including the lipopolysaccharide (LPS) receptors CD14 and TLR4, and also the Fc receptors for IgA and IgG are absent on most intestinal macrophages under homeostatic conditions. Moreover, while macrophages in the intestinal mucosa are refractory to the induction of proinflammatory cytokine secretion, they still display potent phagocytic activity. These adaptations allow intestinal macrophages to comply with their main task, i.e., the efficient removal of microbes while maintaining local tissue homeostasis. In this paper, we review recent findings on the functional differentiation of monocyte subsets into distinct macrophage populations and on the phenotypic and functional adaptations that have evolved in intestinal macrophages in response to their antigen-rich environment. Furthermore, the involvement of intestinal macrophages in the pathogenesis of celiac disease and inflammatory bowel diseases is discussed.


Asunto(s)
Antígenos Bacterianos/inmunología , Bacterias/inmunología , Diferenciación Celular/inmunología , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Animales , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/microbiología , Citocinas/inmunología , Homeostasis/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Receptores de Lipopolisacáridos/inmunología , Macrófagos/patología , Fagocitosis/inmunología , Receptores de IgG/inmunología , Receptor Toll-Like 4/inmunología
12.
J Immunol ; 179(6): 3504-14, 2007 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-17785784

RESUMEN

Efficient induction of mucosal immunity usually employs nasal or oral vaccination while parenteral immunization generally is ineffective at generating mucosal immune responses. This relates to the unique ability of resident mucosal dendritic cells (DC) to induce IgA switching and to imprint mucosa-specific homing receptors on lymphocytes. Based on the well-established plasticity of the DC system, this study sought to investigate whether peripheral DC could be modulated toward "mucosa-type" DC by treatment with immunomodulatory, and therefore potentially adjuvant-like, factors. In this study, we show that monocyte-derived DCs pretreated with the vitamin A derivative all-trans retinoic acid (RA) indeed acquired several attributes characteristic of mucosal DC: secretion of TGF-beta and IL-6 and the capacity to augment mucosal homing receptor expression and IgA responses in cocultured lymphocytes. Addition of a TGF-beta-neutralizing Ab to cocultures significantly inhibited alpha4beta7 integrin, but not CCR9 mRNA expression by the lymphocytes. Both alpha4beta7 integrin and CCR9 mRNA expression, but not IgA production, were suppressed in the presence of a RA receptor antagonist. None of the observed effects on the lymphocytes were influenced by citral, a retinal dehydrogenase inhibitor, arguing against a role for de novo-synthesized RA. Collectively, our findings identified a novel role for RA as a mucosal immune modulator targeting DC. Our results further demonstrate that DC can act as efficient carriers of RA at least in vitro. Consequently, RA targeting of DC shows potential for promoting vaccine-induced mucosal immune responses via a parenteral route of immunization.


Asunto(s)
Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Tretinoina/fisiología , Animales , Transporte Biológico Activo , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/metabolismo , Células Dendríticas/virología , Virus de la Fiebre Aftosa/inmunología , Inmunoglobulina E/biosíntesis , Inmunoglobulina G/biosíntesis , Cadenas beta de Integrinas/biosíntesis , Cadenas beta de Integrinas/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virología , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/virología , ARN Mensajero/biosíntesis , Receptores CCR , Receptores de Quimiocina/biosíntesis , Receptores de Quimiocina/genética , Porcinos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/fisiología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Activación Viral/inmunología
13.
J Immunol ; 171(12): 6334-8, 2003 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-14662829

RESUMEN

NK cell self-tolerance is maintained by inhibitory receptors specific for MHC class I molecules. Inhibitory NK receptors are also expressed on memory CD8 T cells but their biological relevance on T cells is unclear. In this study, we describe the expression of the Ly49A receptor on a subset of autoreactive T cells which persist in mice double-transgenic for the lymphocytic choriomeningitis virus-derived peptide gp33 and a TCRalphabeta specific for the gp33. No Ly49A-expressing cells are found in TCRalphabeta single-transgenic mice, indicating that the presence of the autoantigen is required for Ly49A induction. Direct evidence for an Ag-specific initiation of Ly49A expression has been obtained in vitro after stimulation of autoreactive TCRalphabeta T cells with the cognate self-Ag. This expression of Ly49A substantially reduces Ag-specific activation of autoreactive T cells. These findings thus suggest that autoantigen-specific induction of inhibitory NK cell receptors on T cells may contribute to peripheral self-tolerance.


Asunto(s)
Antígenos Ly/biosíntesis , Autoantígenos/farmacología , Proteínas , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Anticuerpos Bloqueadores/farmacología , Antígenos/biosíntesis , Antígenos Ly/inmunología , Antígenos Ly/fisiología , Antígenos de Superficie , Antígenos Virales/genética , Antígenos Virales/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Glicoproteínas/genética , Glicoproteínas/inmunología , Antígenos H-2/inmunología , Antígenos H-2/metabolismo , Antígeno de Histocompatibilidad H-2D , Memoria Inmunológica/genética , Inmunofenotipificación , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Lectinas Tipo C , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Subfamilia A de Receptores Similares a Lectina de Células NK , Subfamilia B de Receptores Similares a Lectina de Células NK , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Biosíntesis de Proteínas , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores Similares a Lectina de Células NK , Proteínas Virales/genética , Proteínas Virales/inmunología
14.
J Immunol ; 172(7): 4176-83, 2004 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-15034030

RESUMEN

TCRalphabeta CD8alphaalpha intestinal intraepithelial lymphocytes (IEL) represent an enigmatic subset of T cells, particularly, in regard to their potential functions and the apparent persistence of cells expressing self-specific TCR. We have used mice that are transgenic for the TCRalphabeta specific for the lymphocytic choriomeningitis virus (LCMV)-derived peptide gp33, and TCRalphabeta-transgenic mice that coexpress the gp33 Ag ubiquitously, to analyze the functional properties of TCRalphabeta CD8alphaalpha IEL in the presence, or absence, of their specific MHC-restricted Ag, and to assess the impact of molecular mimicry during a potent LCMV infection on potentially self-reactive TCRalphabeta CD8alphaalpha IEL. In this study, we show that the presence of the specific self-Ag results in reduced expression of IL-2, IFN-gamma, and IL-10 by resident TCRalphabeta CD8alphaalpha IEL while expression of mRNA for TGFbeta is not affected. We further demonstrate that despite their secluded location in the epithelium, TCRalphabeta CD8alphaalpha IEL are activated after infection of the intestinal mucosa with LCMV. Importantly, LCMV-induced activation of self-specific TCRalphabeta CD8alphaalpha IEL does not reverse their tolerance as no cytotoxic activity or up-regulated expression of proinflammatory cytokines is detected and no overt signs of autoimmunity are seen. Taken together, these results are in support of an immunoregulatory role for self-specific TCRalphabeta CD8alphaalpha in the intestinal mucosa and clearly speak against an involvement of this cell subset in inflammatory reactions and tissue destruction.


Asunto(s)
Antígenos CD8/biosíntesis , Antígenos de Histocompatibilidad Clase I/fisiología , Mucosa Intestinal/inmunología , Activación de Linfocitos/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Autotolerancia , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos Virales/inmunología , Antígenos CD8/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , División Celular/genética , División Celular/inmunología , Separación Celular/métodos , Células Cultivadas , Citocinas/biosíntesis , Citocinas/genética , Epítopos de Linfocito T/biosíntesis , Perfilación de la Expresión Génica , Glicoproteínas/inmunología , Antígenos de Histocompatibilidad Clase I/biosíntesis , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Activación de Linfocitos/genética , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fragmentos de Péptidos/inmunología , Autotolerancia/genética , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/virología , Proteínas Virales/inmunología
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