RESUMEN
OBJECTIVE: Histamine derived from mast cells and basophils plays important roles in inducing allergic symptoms. Although T cells also produce histamine, the involvement of the histamine produced from T cells has remained enigmatic. We sought to reveal the roles of T helper 2 (Th2) cell-derived histamine in nasal allergic disorders. METHODS: The histamine production from Th2 cells was measured by EIA. The mRNA expression of histidine decarboxylase (HDC) was measured by real-time PCR. To investigate the roles of Th2 cell-derived histamine in vivo, we analyzed an antigen-specific Th2 cell transfer mouse model. RESULTS: Th2 cells produced histamine by T cell receptor stimulation, and these properties were specific for Th2 cells, but not Th1 cells and naïve CD4 T cells. The histamine produced from Th2 cells was involved in the infiltrations of Th2 cells in response to antigen exposure. CONCLUSION: These results suggest that Th2 cell-derived histamine play important roles in nasal allergic disorders.
Asunto(s)
Histamina/inmunología , Mucosa Nasal/inmunología , Rinitis Alérgica/inmunología , Células Th2/inmunología , Alérgenos/inmunología , Animales , Movimiento Celular , Histidina Descarboxilasa/genética , Ratones Endogámicos BALB C , Ratones Noqueados , Ovalbúmina/inmunología , Células Th2/fisiología , Células Th2/trasplanteRESUMEN
IL-9 is involved in various T cell-dependent inflammatory models including colitis, encepahlitis, and asthma. However, the regulation and specificity of IL-9 responsiveness by T cells during immune responses remains poorly understood. Here, we addressed this question using two different models: experimental colitis induced by transfer of naive CD4+ CD45RBhigh T cells into immunodeficient mice, and OVA-specific T cell activation. In the colitis model, constitutive IL-9 expression exacerbated inflammation upon transfer of CD4+ CD45RBhigh T cells from WT but not from Il9r-/- mice, indicating that IL-9 acts directly on T cells. Suprisingly, such naïve CD4+ CD45RBhigh T cells failed to express the Il9r or respond to IL-9 in vitro, in contrast with CD4+ CD45RBlow T cells. By using OVA-specific T cells, we observed that T cells acquired the capacity to respond to IL-9 along with CD44 upregulation, after long-lasting (5 to 12 days) in vivo antigenic stimulation. Il9r expression was associated with Th2 and Th17 phenotypes. Interestingly, in contrast to the IL-2 response, antigen restimulation downregulated IL-9 responsiveness. Taken together, our results demonstrate that IL-9 does not act on naïve T cells but that IL-9 responsiveness is acquired by CD4+ T cells after in vivo activation and acquisition of memory markers such as CD44.
Asunto(s)
Traslado Adoptivo/efectos adversos , Colitis/inmunología , Interleucina-9/inmunología , Células Th17/inmunología , Células Th2/inmunología , Animales , Colitis/etiología , Colitis/genética , Colitis/patología , Modelos Animales de Enfermedad , Receptores de Hialuranos/genética , Receptores de Hialuranos/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-9/genética , Ratones , Ratones Noqueados , Ratones SCID , Receptores de Interleucina-9/genética , Receptores de Interleucina-9/inmunología , Células Th17/patología , Células Th17/trasplante , Células Th2/patología , Células Th2/trasplanteRESUMEN
With emerging evidence on the importance of non-cell autonomous toxicity in neurodegenerative diseases, therapeutic strategies targeting modulation of key immune cells. including microglia and Treg cells, have been designed for treatment of ALS and other neurodegenerative diseases. Strategy switching the patient's environment from a pro-inflammatory toxic to an anti-inflammatory, and neuroprotective condition, could be potential therapy for neurodegenerative diseases. Mesenchymal stem cells (MSCs) regulate innate and adaptive immune cells, through release of soluble factors such as TGF-ß and elevation of regulatory T cells (Tregs) and T helper-2 cells (Th2 cells), would play important roles, in the neuroprotective effect on motor neuronal cell death mechanisms in ALS. Single cycle of repeated intrathecal injections of BM-MSCs demonstrated a clinical benefit lasting at least 6 months, with safety, in ALS patients. Cytokine profiles of CSF provided evidence that BM-MSCs, have a role in switching from pro-inflammatory to anti-inflammatory conditions. Inverse correlation of TGF-ß1 and MCP-1 levels, could be a potential biomarker to responsiveness. Thus, additional cycles of BM-MSC treatment are required, to confirm long-term efficacy and safety. [BMB Reports 2018; 51(11): 545-546].
Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , Inmunomodulación , Inflamación/inmunología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/fisiología , Enfermedades Neurodegenerativas/terapia , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/patología , Muerte Celular/inmunología , Humanos , Trasplante de Células Madre Mesenquimatosas/métodos , Neuronas Motoras/patología , Neuronas Motoras/fisiología , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/patología , Linfocitos T Reguladores/fisiología , Linfocitos T Reguladores/trasplante , Células Th2/fisiología , Células Th2/trasplanteRESUMEN
Background and aims: The aberrant immune responses play a critical role in the pathogenesis of myocarditis. Vitamin D receptor (VDR) has immune regulatory functions. This study aims to investigate the role of VDR in restricting the immune inflammation in the heart. Methods and results: The human heart samples were obtained from the heart transplantation. T helper (Th)2 and Th1 responses in the heart tissue were characterized by histology and immune assay. VDR-/- mice and recombination activating gene 2-/- mice were used in the experiments to test the role of VDR in maintaining the homeostasis in the heart. The results showed that, besides tissue damage, lower expression of VDR, high frequency of Th2 cells and increase in Th2 cytokines in the hearts of patients with myocarditis at the end stage of heart failure. The spontaneous Th2-biased inflammation was observed in the hearts of VDR-/- mice. CD4+ T cells from the VDR-/- mouse hearts were at highly activating status. The naïve VDR-/- CD4+ T cells and naïve CD4+ T cells from human hearts with myocarditis were prone to differentiate into Th2 cells. VDR formed complexes with GATA3, the interleukin (IL)-4 transcription factor, to prevent the Il4 gene transcription. Transplantation with VDR-/-CD4+ T cells induced the Th2-biased inflammation in the hearts of Rag2-/- mice. Reconstitution of VDR in CD4+ T cells inhibited the Th2-biased inflammation in the heart. Conclusions: VDR-deficiency contributes to the pathogenesis of myocarditis. To enhance the VDR expression in CD4+, T cells haves the therapeutic potential for the treatment of myocarditis.
Asunto(s)
Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Miocarditis/prevención & control , Miocitos Cardíacos/metabolismo , Receptores de Calcitriol/metabolismo , Células Th2/metabolismo , Traslado Adoptivo , Adulto , Animales , Diferenciación Celular , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Femenino , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/inmunología , Factor de Transcripción GATA3/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-4/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Miocarditis/genética , Miocarditis/inmunología , Miocarditis/metabolismo , Miocitos Cardíacos/inmunología , Miocitos Cardíacos/patología , Fenotipo , Receptores de Calcitriol/genética , Receptores de Calcitriol/inmunología , Transducción de Señal , Células Th2/inmunología , Células Th2/trasplante , Adulto JovenRESUMEN
BACKGROUND: Asthmatic and allergic inflammation is mediated by TH2 cytokines (IL-4, IL-5, and IL-13). Although we have learned much about how TH2 cells are differentiated, the TH2 checkpoint mechanisms remain elusive. OBJECTIVES: In this study we investigate how monocyte chemotactic protein-induced protein 1 (MCPIP1; encoded by the Zc3h12a gene) regulates IL-5-producing TH2 cell differentiation and TH2-mediated inflammation. METHODS: The functions of Zc3h12a-/- CD4 T cells were evaluated by checking the expression of TH2 cytokines and transcription factors in vivo and in vitro. Allergic airway inflammation of Zc3h12a-/- mice was examined with murine asthma models. In addition, antigen-specific CD4 T cells deficient in MCPIP1 were transferred to wild-type recipient mice, challenged with ovalbumin (OVA) or house dust mite (HDM), and accessed for TH2 inflammation. RESULTS: Zc3h12a-/- mice have spontaneous severe lung inflammation, with an increase in mainly IL-5- and IL-13-producing but not IL-4-producing TH2 cells in the lung. Mechanistically, differentiation of IL-5-producing Zc3h12a-/- TH2 cells is mediated through Notch signaling and Gata3 independent of IL-4. Gata3 mRNA is stabilized in Zc3h12a-/- TH2 cells. MCPIP1 promotes Gata3 mRNA decay through the RNase domain. Furthermore, deletion of MCPIP1 in OVA- or HDM-specific T cells leads to significantly increased TH2-mediated airway inflammation in OVA or HDM murine models of asthma. CONCLUSIONS: Our study reveals that MCPIP1 regulates the development and function of IL-5-producing TH2 cells through the Notch/Gata3 pathway. MCPIP1 represents a new and promising target for the treatment of asthma and other TH2-mediated diseases.
Asunto(s)
Asma/inmunología , Inflamación/inmunología , Hipersensibilidad Respiratoria/inmunología , Ribonucleasas/metabolismo , Células Th2/inmunología , Traslado Adoptivo , Animales , Diferenciación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Factor de Transcripción GATA3/metabolismo , Humanos , Terapia de Inmunosupresión , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Notch/metabolismo , Ribonucleasas/genética , Transducción de Señal , Células Th2/trasplanteRESUMEN
The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the TH2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection.
Asunto(s)
Asma/terapia , Macrófagos Alveolares/inmunología , Monocitos/inmunología , Pyroglyphidae/inmunología , Rhadinovirus/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Asma/inmunología , Línea Celular , Cricetinae , Células Dendríticas/inmunología , Femenino , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Macrófagos Alveolares/citología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Células Th2/trasplanteRESUMEN
Poly-ADP ribose polymerase-14 (PARP14 or ARTD8) was initially identified as a transcriptional co-activator for signal transducer and activator of transcription 6 (Stat6), where the presence of interleukin-4 (IL-4) and activated Stat6 induces the enzymatic activity of PARP14 that promotes T helper type 2 differentiation and allergic airway disease. To further our understanding of PARP14 in allergic disease, we studied the function of PARP14 in allergic inflammation of skin using mice that express constitutively active Stat6 in T cells (Stat6VT) and develop spontaneous inflammation of the skin. We mated Stat6VT mice to Parp14-/- mice and observed that approximately 75% of the Stat6VT × Parp14-/- mice develop severe atopic dermatitis (AD)-like lesions, compared with about 50% of Stat6VT mice, and have increased morbidity compared with Stat6VT mice. Despite this, gene expression in the skin and the cellular infiltrates was only modestly altered by the absence of PARP14. In contrast, we saw significant changes in systemic T-cell cytokine production. Moreover, adoptive transfer experiments demonstrated that decreases in IL-4 production reflected a cell intrinsic role for PARP14 in Th2 cytokine control. Hence, our data suggest that although PARP14 has similar effects on T-cell cytokine production in several allergic disease models, the outcome of those effects is distinct, depending on the target organ of disease.
Asunto(s)
Dermatitis Atópica/prevención & control , Poli(ADP-Ribosa) Polimerasas/metabolismo , Factor de Transcripción STAT6/metabolismo , Piel/enzimología , Traslado Adoptivo , Animales , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Dermatitis Atópica/enzimología , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/genética , Queratinocitos/inmunología , Queratinocitos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Fosforilación , Poli(ADP-Ribosa) Polimerasas/deficiencia , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/inmunología , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/inmunología , Índice de Severidad de la Enfermedad , Transducción de Señal , Piel/inmunología , Piel/patología , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/trasplante , TirosinaRESUMEN
Immunodeficient mice transplanted with human peripheral blood mononuclear cells (PBMCs) are promising tools to evaluate human immune responses to vaccines. However, these mice usually develop severe graft-versus-host disease (GVHD), which makes estimation of antigen-specific IgG production after antigen immunization difficult. To evaluate antigen-specific IgG responses in PBMC-transplanted immunodeficient mice, we developed a novel NOD/Shi-scid-IL2rγnull (NOG) mouse strain that systemically expresses the human IL-4 gene (NOG-hIL-4-Tg). After human PBMC transplantation, GVHD symptoms were significantly suppressed in NOG-hIL-4-Tg compared to conventional NOG mice. In kinetic analyses of human leukocytes, long-term engraftment of human T cells has been observed in peripheral blood of NOG-hIL-4-Tg, followed by dominant CD4+ T rather than CD8+ T cell proliferation. Furthermore, these CD4+ T cells shifted to type 2 helper (Th2) cells, resulting in long-term suppression of GVHD. Most of the human B cells detected in the transplanted mice had a plasmablast phenotype. Vaccination with HER2 multiple antigen peptide (CH401MAP) or keyhole limpet hemocyanin (KLH) successfully induced antigen-specific IgG production in PBMC-transplanted NOG-hIL-4-Tg. The HLA haplotype of donor PBMCs might not be relevant to the antibody secretion ability after immunization. These results suggest that the human PBMC-transplanted NOG-hIL-4-Tg mouse is an effective tool to evaluate the production of antigen-specific IgG antibodies.
Asunto(s)
Anticuerpos Antineoplásicos/inmunología , Formación de Anticuerpos , Proteínas Portadoras/inmunología , Inmunización , Inmunoglobulina G/inmunología , Interleucina-4/inmunología , Péptidos/farmacología , Receptor ErbB-2/farmacología , Animales , Anticuerpos Antineoplásicos/genética , Linfocitos B/inmunología , Linfocitos B/trasplante , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Proteínas Portadoras/genética , Xenoinjertos , Humanos , Inmunoglobulina G/genética , Interleucina-4/genética , Ratones , Ratones SCID , Ratones Transgénicos , Péptidos/inmunología , Receptor ErbB-2/inmunología , Células Th2/inmunología , Células Th2/trasplanteRESUMEN
We evaluated the immunological status of patients with various solid tumors by flow cytometry of immune cell populations and their frequencies in peripheral blood samples. The change in immunological status was also analyzed in patients given autologous immune cell therapy, such as αßT cell, γδT cell, NK cell or DC vaccine therapy. The frequency of regulatory T-cells (Tregs) was shown to be high in patients with cancers of the lung (squamous carcinoma cells), head and neck, esophagus and uterus, although there were no significant differences in effector cell population or Th1/2 ratio between various types of cancers except for a few. The cellular immunological status was impaired in most patients with advanced solid tumors before immune cell therapy and the impaired T-cell immune status was restored by infusion of effector cells, such as αßT cells or γδT cells, although the number of NK cells in the peripheral blood did not always increase after autologous NK cell therapy. The concurrent αßT cell therapy and DC vaccine therapy could successfully increase the number of CD8(+) T-cells in the peripheral blood of patients with various types of cancers. Two or three injections of αßT cells could potentially reduce Tregs frequency prior to DC vaccine, as well as the concurrent αßT cell and DC vaccine therapy. However, an increase in the Tregs frequency was observed in some patients who received NK cell therapy. These findings suggest that it is necessary to include or combine certain types of immune cell therapy when the Tregs frequency of cancer patients is high before or after autologous immune cell therapy.
Asunto(s)
Células Dendríticas/trasplante , Inmunoterapia Adoptiva , Células Asesinas Naturales/trasplante , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T/trasplante , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Vacunas contra el Cáncer/inmunología , Femenino , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/trasplante , Células TH1/inmunología , Células TH1/trasplante , Células Th2/inmunología , Células Th2/trasplante , Trasplante AutólogoRESUMEN
Neonatal immunity exhibits weak Th1 but excessive Th2 responses, and the underlying mechanisms remain elusive. In this article, we show that neonatal basophils readily produce IL-4, a cytokine that proved to be pivotal in shaping the programs of both lymphocyte subsets. Besides promoting Th2 programs, IL-4 is captured by the IL-4 heteroreceptor (IL-4Rα/IL-13Rα1) expressed on dendritic cells and instigates IL-12 downregulation. Under these circumstances, differentiating Th1 cells upregulate IL-13Rα1, leading to an unusual expression of the heteroreceptor, which will serve as a death marker for these Th1 cells during rechallenge with Ag. The resulting Th1/Th2 imbalance impacts childhood immunity culminating in sensitivity to allergic reactions, susceptibility to microbial infection and perhaps poor efficacy of pediatric vaccines.
Asunto(s)
Basófilos/inmunología , Células Dendríticas/inmunología , Regulación del Desarrollo de la Expresión Génica/inmunología , Células TH1/inmunología , Células Th2/inmunología , Traslado Adoptivo , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Basófilos/citología , Basófilos/efectos de los fármacos , Basófilos/trasplante , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/trasplante , Femenino , Inmunidad Innata , Interleucina-12/genética , Interleucina-12/inmunología , Subunidad alfa1 del Receptor de Interleucina-13/genética , Subunidad alfa1 del Receptor de Interleucina-13/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Datos de Secuencia Molecular , Ovalbúmina/farmacología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Transducción de Señal , Células TH1/citología , Células TH1/efectos de los fármacos , Células TH1/trasplante , Células Th2/citología , Células Th2/efectos de los fármacos , Células Th2/trasplanteRESUMEN
In atopic dermatitis (AD), the inflammatory response between skin-infiltrating T cells and keratinocytes is fundamental to the development of chronic lesional eczema. The aim of this study was to investigate whether skin-derived T cells from AD patients could induce an inflammatory response in mice through keratinocyte activation and consequently cause the development of eczematous lesions. Punch biopsies of the lesional skin from AD patients were used to establish skin-derived T cell cultures, which were transferred to NOD.Cg-Prkd(scid) Il2rg(tm1Sug) /JicTac (NOG) mice. We found that the subcutaneous injection of the human AD skin-derived T cells resulted in the migration of the human T cells from subcutis to the papillary dermis followed by the development of erythema and oedema in the mouse skin. Furthermore, the human T cells induced a transient proliferative response in the mouse keratinocytes shown as increased numbers of Ki-67(+) keratinocytes and increased epidermal thickness. Out of six established AD skin-derived T cell cultures, two were superior at inducing a skin reaction in the mice, and these cultures were found to contain >10% CCR10(+) T cells compared to <2% for the other cultures. In comparison, blood-derived in vitro-differentiated Th2 cells only induced a weak response in a few of the mice. Thus, we conclude that human AD skin-derived T cells can induce a reaction in the mouse skin through the induction of a proliferative response in the mouse keratinocytes.
Asunto(s)
Dermatitis Atópica/inmunología , Queratinocitos/inmunología , Piel/inmunología , Células Th2/inmunología , Células Th2/trasplante , Adulto , Animales , Relación CD4-CD8 , Calgranulina A/biosíntesis , Movimiento Celular/inmunología , Proliferación Celular , Eccema/inmunología , Femenino , Humanos , Inflamación/inmunología , Interleucina-2/farmacología , Interleucina-4/farmacología , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Piel/citología , Trasplante Heterólogo , Adulto JovenRESUMEN
BACKGROUND: IL-9 is important for the growth and survival of mast cells. IL-9 is produced by T cells, natural killer T cells, mast cells, eosinophils, and innate lymphoid cells, although the cells required for mast cell accumulation during allergic inflammation remain undefined. OBJECTIVE: We sought to elucidate the role of TH9 cells in promoting mast cell accumulation in models of allergic lung inflammation. METHODS: Adoptive transfer of ovalbumin-specific TH2 and TH9 cells was used to assess the ability of each subset to mediate mast cell accumulation in tissues. Mast cell accumulation was assessed in wild-type mice and mice with PU.1-deficient T cells subjected to acute and chronic models of allergic inflammation. RESULTS: Adoptive transfer experiments demonstrated that recipients of TH9 cells had significantly higher mast cell accumulation and expression of mast cell proteases compared with control or TH2 recipients. Mast cell accumulation was dependent on IL-9, but not IL-13, a cytokine required for many aspects of allergic inflammation. In models of acute and chronic allergic inflammation, decreased IL-9 levels in mice with PU.1-deficient T cells corresponded to diminished tissue mast cell numbers and expression of mast cell proteases. Mice with PU.1-deficient T cells have defects in IL-9 production from CD4(+) T cells, but not natural killer T cells or innate lymphoid cells, suggesting a TH cell-dependent phenotype. Rag1(-/-) mice subjected to a chronic model of allergic inflammation displayed reduced mast cell infiltration comparable with accumulation in mice with PU.1-deficient T cells, emphasizing the importance of IL-9 produced by T cells in mast cell recruitment. CONCLUSION: TH9 cells are a major source of IL-9 in models of allergic inflammation and play an important role in mast cell accumulation and activation.
Asunto(s)
Hipersensibilidad al Huevo/inmunología , Interleucina-9/inmunología , Mastocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Linaje de la Célula/inmunología , Movimiento Celular , Hipersensibilidad al Huevo/genética , Hipersensibilidad al Huevo/patología , Femenino , Eliminación de Gen , Regulación de la Expresión Génica , Genotipo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-9/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Mastocitos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovalbúmina , Fenotipo , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/inmunología , Transducción de Señal , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Colaboradores-Inductores/trasplante , Células Th2/patología , Células Th2/trasplante , Transactivadores/deficiencia , Transactivadores/genética , Transactivadores/inmunologíaRESUMEN
BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key factor in the development of allergic asthma. Numbers of TH2 memory cells gradually increase in allergic patients with the progression of disease and persist in the lungs during remission, although the mechanism is not clear. OBJECTIVE: We sought to define the role of TSLP in TH2 memory cell generation and maintenance in vivo. METHODS: Adoptive transfer of wild-type and thymic stromal lymphopoietin receptor (TSLPR)-deficient ovalbumin-specific CD4(+) T cells before TH2 sensitization was used to define T cell-specific TSLP effects. Atopic dermatitis and increased serum TSLP concentrations were induced by topical application of the vitamin D3 analog MC903. Memory cells in peripheral blood were monitored weekly with flow cytometry. Memory recall was tested after intranasal ovalbumin challenge. RESULTS: TSLP signaling in CD4(+) T cells is required for the generation/maintenance of memory cells after in vivo priming. TSLPR-deficient CD4(+) T cells have no defects in proliferation but do not survive 1 week after sensitization, and increased TSLP expression during sensitization significantly increased the frequency of memory cells. Although in vitro-differentiated TSLPR-deficient TH2 cells develop into memory cells with equal efficiency to wild-type cells, the recall response to airway antigen challenge is impaired. Moreover, after antigen challenge of mice with established TH2 memory, TSLP signaling in CD4(+) T cells significantly affects memory cell generation/maintenance from secondary effector cells. CONCLUSION: TSLP signaling in CD4(+) T cells is required for not only TH2 memory cell formation in vivo but also the recall response of the memory cells to local antigen challenge.
Asunto(s)
Inmunidad Adaptativa , Citocinas/inmunología , Dermatitis Atópica/inmunología , Inmunidad Innata , Células Th2/inmunología , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Líquido del Lavado Bronquioalveolar/citología , Calcitriol/análogos & derivados , Diferenciación Celular , Citocinas/deficiencia , Citocinas/genética , Células Dendríticas/inmunología , Células Dendríticas/patología , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/genética , Dermatitis Atópica/patología , Femenino , Regulación de la Expresión Génica , Memoria Inmunológica , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Ovalbúmina/administración & dosificación , Transducción de Señal , Células Th2/patología , Células Th2/trasplante , Linfopoyetina del Estroma TímicoRESUMEN
Via the histamine H4 -receptor (H4 R), histamine promotes the pathogenesis of experimental allergic asthma in mice. Application of H4 R antagonists during sensitization as well as during provocation reduces the severity of the disease. However, the specific cell types functionally expressing H4 R in experimental allergic asthma have not been well characterized in vivo. In this study, we identified the cell type(s) responsible for H4 R activity in experimental asthma and related physiological mechanisms. Using H4 R-deficient mice, we studied the role of H4 R in the sensitization and effector phase. DCs lacking H4 R expression during the in vitro sensitization reaction resulted in effector T cells unable to induce an entire eosinophilic inflammation in the lung upon adoptive transfer in vivo. Recipient mice lacking H4 R expression, which were adoptively transferred with H4 R(+/+) T cells polarized in the presence of H4 R(+/+) DCs, showed reduced signs of inflammation and ameliorated lung function. Here, we provide in vivo evidence that in experimental asthma in mice the H4 R specifically regulates activation of DCs during sensitization, while in the effector phase the H4 R is active in cells involved in the activation of eosinophils, and possibly other cells. A putative therapy targeting the H4 R may be an option for asthma patients developing IL-5-dependent eosinophilia.
Asunto(s)
Asma/inmunología , Células Dendríticas/inmunología , Eosinófilos/inmunología , Inflamación/inmunología , Receptores Acoplados a Proteínas G/inmunología , Receptores Histamínicos/inmunología , Traslado Adoptivo , Alérgenos/inmunología , Animales , Asma/inducido químicamente , Asma/patología , Líquido del Lavado Bronquioalveolar/citología , Antígeno CD11c/metabolismo , Citocinas/inmunología , Modelos Animales de Enfermedad , Histamina/metabolismo , Interleucina-5/inmunología , Pulmón/inmunología , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ovalbúmina , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/genética , Receptores Histamínicos/genética , Receptores Histamínicos H4 , Células Th2/inmunología , Células Th2/trasplanteRESUMEN
Mycoplasmas are a common cause of pneumonia in humans and animals, and attempts to create vaccines have not only failed to generate protective host responses, but they have exacerbated the disease. Mycoplasma pulmonis causes a chronic inflammatory lung disease resulting from a persistent infection, similar to other mycoplasma respiratory diseases. Using this model, Th1 subsets promote resistance to mycoplasma disease and infection, whereas Th2 responses contribute to immunopathology. The purpose of the present study was to evaluate the capacity of cytokine-differentiated dendritic cell (DC) populations to influence the generation of protective and/or pathologic immune responses during M. pulmonis respiratory disease in BALB/c mice. We hypothesized that intratracheal inoculation of mycoplasma Ag-pulsed bone marrow-derived DCs could result in the generation of protective T cell responses during mycoplasma infection. However, intratracheal inoculation (priming) of mice with Ag-pulsed DCs resulted in enhanced pathology in the recipient mice when challenged with mycoplasma. Inoculation of immunodeficient SCID mice with Ag-pulsed DCs demonstrated that this effect was dependent on lymphocyte responses. Similar results were observed when mice were primed with Ag-pulsed pulmonary, but not splenic, DCs. Lymphocytes generated in uninfected mice after the transfer of either Ag-pulsed bone marrow-derived DCs or pulmonary DCs were shown to be IL-13(+) Th2 cells, known to be associated with immunopathology. Thus, resident pulmonary DCs most likely promote the development of immunopathology in mycoplasma disease through the generation of mycoplasma-specific Th2 responses. Vaccination strategies that disrupt or bypass this process could potentially result in a more effective vaccination.
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Antígenos Bacterianos/administración & dosificación , Células de la Médula Ósea/inmunología , Células Dendríticas/inmunología , Pulmón/inmunología , Mycoplasma pulmonis/inmunología , Neumonía por Mycoplasma/inmunología , Células Th2/inmunología , Administración Intranasal , Animales , Células de la Médula Ósea/microbiología , Células de la Médula Ósea/patología , Células Dendríticas/patología , Células Dendríticas/trasplante , Femenino , Intubación Intratraqueal , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Mycoplasma pulmonis/patogenicidad , Neumonía por Mycoplasma/microbiología , Neumonía por Mycoplasma/patología , Células Th2/patología , Células Th2/trasplanteRESUMEN
In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4(+) T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4(+) Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4(+) Th2 and Th1 cells relative to regulatory T cells and CD8(+) T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens.
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Linfocitos T CD4-Positivos/trasplante , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Transfusión de Linfocitos/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Resistencia a Medicamentos/inmunología , Femenino , Perfilación de la Expresión Génica , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Neoplasias Hematológicas/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Inducción de Remisión , Sirolimus/administración & dosificación , Sirolimus/farmacología , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/trasplante , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/trasplante , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Alzheimer's disease (AD) is characterized by the presence of amyloid-ß (Aß)-containing plaques, neurofibrillary tangles, and neuronal loss in the brain. Inflammatory changes, typified by activated microglia, particularly adjacent to Aß plaques, are also a characteristic of the disease, but it is unclear whether these contribute to the pathogenesis of AD or are a consequence of the progressive neurodegenerative processes. Furthermore, the factors that drive the inflammation and neurodegeneration remain poorly understood. CNS-infiltrating T cells play a pivotal role in the pathogenesis of multiple sclerosis, but their role in the progression of AD is still unclear. In this study, we examined the role of Aß-specific T cells on Aß accumulation in transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1). We found significant infiltration of T cells in the brains of APP/PS1 mice, and a proportion of these cells secreted IFN-γ or IL-17. Aß-specific CD4 T cells generated by immunization with Aß and a TLR agonist and polarized in vitro to Th1-, Th2-, or IL-17-producing CD4(+) T cells, were adoptively transferred to APP/PS1 mice at 6 to 7 mo of age. Assessment of animals 5 wk later revealed that Th1 cells, but not Th2 or IL-17-producing CD4(+) T cells, increased microglial activation and Aß deposition, and that these changes were associated with impaired cognitive function. The effects of Th1 cells were attenuated by treatment of the APP/PS1 mice with an anti-IFN-γ Ab. Our study suggests that release of IFN-γ from infiltrating Th1 cells significantly accelerates markers of diseases in an animal model of AD.
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Enfermedad de Alzheimer/inmunología , Péptidos beta-Amiloides/genética , Encéfalo/inmunología , Interferón gamma/inmunología , Microglía/inmunología , Placa Amiloide/patología , Células TH1/inmunología , Traslado Adoptivo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/inmunología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/inmunología , Animales , Anticuerpos/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Expresión Génica , Interferón gamma/antagonistas & inhibidores , Interferón gamma/metabolismo , Interleucina-17/genética , Interleucina-17/inmunología , Ratones , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/patología , Placa Amiloide/inmunología , Presenilina-1/genética , Presenilina-1/inmunología , Células TH1/patología , Células TH1/trasplante , Células Th17/inmunología , Células Th17/patología , Células Th17/trasplante , Células Th2/inmunología , Células Th2/patología , Células Th2/trasplanteRESUMEN
The role of T lymphocytes in central nervous system (CNS) injuries is controversial, with inconsistent results reported concerning the effects of T-lymphocyte transfer on spinal cord injury (SCI). Here, we demonstrate that a specific T-lymphocyte subset enhances functional recovery after contusion SCI in mice. Intraperitoneal adoptive transfer of type 1 helper T (Th1)-conditioned cells 4 days after SCI promoted recovery of locomotor activity and tactile sensation and concomitantly induced regrowth of corticospinal tract and serotonergic fibers. However, neither type 2 helper T (Th2)- nor IL-17-producing helper T (Th17)-conditioned cells had such effects. Activation of microglia and macrophages were observed in the spinal cords of Th1-transfered mice after SCI. Specifically, M2 subtype of microglia/macrophages was upregulated after Th1 cell transfer. Neutralization of interleukin 10 secreted by Th1-conditioned cells significantly attenuated the beneficial effects by Th1-conditioned lymphocytes after SCI. We also found that Th1-conditioned lymphocytes secreted significantly higher levels of neurotrophic factor, neurotrophin 3 (NT-3), than Th2- or Th17-conditioned cells. Thus, adoptive transfer of pro-inflammatory Th1-conditioned cells has neuroprotective effects after SCI, with prospective implications in immunomodulatory treatment of CNS injury.
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Traslado Adoptivo , Axones/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Células TH1/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Microglía/citología , Microglía/metabolismo , Actividad Motora , Neurotrofina 3/metabolismo , Recuperación de la Función , Células TH1/inmunología , Células TH1/trasplante , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/trasplante , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/trasplante , TactoRESUMEN
BACKGROUND: The IL-1 family cytokine IL-33 is involved in the induction of airway inflammation in allergic patients and after viral infection. Several cell types, including CD4(+) T(H)2 cells and the recently described type 2 innate lymphoid cells (ILCs), are targets for IL-33, yet the mechanisms by which this cytokine modulates their activation are not clear. OBJECTIVES: Our goal was to investigate a role for mammalian target of rapamycin (mTOR) signaling in the activation of T(H)2 and ILC responses and the induction of airway inflammation by IL-33. METHODS: We biochemically determined the effect of IL-33 on mTOR activation in T(H)2 cells and ILCs and examined the effect of this signaling pathway in vivo using a murine model of IL-33-induced lung inflammation. RESULTS: We found that IL-33 induces mTOR activation through p110δ phosphoinositide 3-kinase and that blockade of the mTOR pathway inhibited IL-33-induced IL-5 and IL-13 production by T(H)2 cells and ILCs. Furthermore, use of a ribosomal protein S6 kinase 1 inhibitor implicated a role for ribosomal protein S6 kinase 1 in IL-33-induced mTOR-dependent cytokine production. Intranasal administration of IL-33 to wild-type mice induced airway inflammation, whereas adoptive transfer of wild-type ILCs to IL-33 receptor-deficient (St2(-/-)) mice recapitulated this response. Importantly, coadministration of the mTOR inhibitor rapamycin reduced IL-33-dependent ILC, macrophage, and eosinophil accumulation; cytokine secretion; and mucus deposition in the airways. CONCLUSION: These data reveal a hitherto unrecognized role of mTOR signaling in IL-33-driven, ILC-dependent inflammation in vivo and suggest that manipulation of this pathway might represent a target for therapeutic intervention for airway inflammation.
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Interleucinas/administración & dosificación , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Serina-Treonina Quinasas TOR/metabolismo , Células Th2/efectos de los fármacos , Animales , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/genética , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/genética , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-13/metabolismo , Interleucina-33 , Interleucina-5/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neumonía/inducido químicamente , Receptores de Interleucina/genética , Proteínas Quinasas S6 Ribosómicas/metabolismo , Transducción de Señal/efectos de los fármacos , Células Th2/inmunología , Células Th2/trasplanteRESUMEN
BACKGROUND & AIMS: Induction of colitis in mice by administration of oxazolone is mediated by T-helper (Th) 2 cells and has features of human ulcerative colitis. We investigated whether activation of interleukin (IL)-4Rα on T and B cells determines their effector functions and mediates oxazolone-induced colitis. METHODS: We studied induction of colitis with oxazolone in wild-type mice and those with CD4(+) T cells that did not express IL-4Rα (Lck(cre)IL-4Rα(-/lox)). We also generated mice with B cells that did not express IL-4Rα (mb1(cre)IL-4Rα(-/lox)) and studied induction of colitis. RESULTS: Lck(cre)IL-4Rα(-/lox) mice did not develop colitis in response to oxazolone, and their levels of IL-4, IL-13, and immunoglobulin (Ig) E were reduced. Adoptive transfer of naïve, wild-type CD4(+) Th cells depleted of natural killer T cells to Lck(cre)IL-4Rα(-/lox) mice restored their susceptibility to colitis. In contrast, Lck(cre)IL-4Rα(-/lox) mice maintained their protection against colitis when IL-13-deficient CD4(+) T cells were transferred. These findings indicate that development of colitis involves not only natural killer T-cell functions, but also requires IL-13 production by CD4(+) T helper cells. Mb1(cre)IL-4Rα(-/lox) mice, which cannot produce IgE, were also protected against oxazolone-induced colitis. Blocking IgE binding significantly reduced mast cell numbers in colons and protected wild-type BALB/c mice from the onset of colitis. CONCLUSIONS: IL-4 appears to induce CD4(+) Th2 cells to produce IL-13 and B cells to produce IgE, which together mediate oxazolone-induced colitis in mice.