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1.
Immunity ; 43(1): 175-86, 2015 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-26200013

RESUMO

House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells.


Assuntos
Inflamação/imunologia , Interleucina-2/imunologia , Interleucinas/imunologia , Mastócitos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Células Cultivadas , Eosinofilia/induzido quimicamente , Humanos , Interleucina-10/imunologia , Interleucina-2/genética , Interleucina-33 , Interleucinas/genética , Interleucinas/farmacologia , Pulmão/citologia , Pulmão/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Papaína/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Pyroglyphidae/imunologia , Células Th2/imunologia
2.
Diabetologia ; 65(7): 1185-1197, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35511238

RESUMO

AIMS/HYPOTHESIS: Immunomodulators blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have improved the treatment of a broad spectrum of cancers. These immune checkpoint inhibitors (ICIs) reactivate the immune system against tumour cells but can also trigger autoimmune side effects, including type 1 diabetes. Mesenchymal stem cell (MSC) therapy is the most prevalent cell therapy, with tissue-regenerating, anti-fibrosis and immunomodulatory functions provided by the secretome of the cells. Here, we examined whether systemic MSC treatment could prevent the development of type 1 diabetes in a NOD mouse model. METHODS: The purified PD-L1 monoclonal antibody was administered to induce diabetes in male NOD mice which normally do not develop diabetes. Human adipose-derived MSCs were administered by tail vein injections. T cells, macrophages and monocyte-derived macrophages expressing C-X-C motif chemokine ligand 9 (CXCL9) in pancreatic sections of NOD mice and a cancer patient who developed diabetes following the ICI treatments were analysed by immunofluorescence. Tissue localisation of the injected MSCs, plasma exosome levels and plasma cytokine profiles were also investigated. RESULTS: PD-1/PD-L1 blockade induced diabetes in 16 of 25 (64%) NOD mice which received anti-PD-L1 mAb without hMSCs [MSC(-)], whereas MSC administration decreased the incidence to four of 21 (19%) NOD mice which received anti-PD-L1 mAb and hMSCs [MSC(+)]. The PD-1/PD-L1 blockade significantly increased the area of CD3-positive T cells (6.2-fold) and macrophage-2 (Mac-2) antigen (2.5-fold)- and CXCL9 (40.3-fold)-positive macrophages in the islets. MSCs significantly reduced T cell (45%) and CXCL9-positive macrophage (67%) accumulation in the islets and the occurrence of diabetes. The insulin content (1.9-fold) and islet beta cell area (2.7-fold) were also improved by MSCs. T cells and CXCL9-positive macrophages infiltrated into the intricate gaps between the beta cells in the islets by PD-1/PD-L1 blockade. Such immune cell infiltration was largely prevented by MSCs. The most striking difference was observed in the CXCL9-positive macrophages, which normally did not reside in the beta cell region in the islets but abundantly accumulated in this area after PD-1/PD-L1 blockade and were prevented by MSCs. The CXCL9-positive macrophages were also observed in the islets of a cancer patient who developed diabetes following the administration of ICIs but few CXCL9-positive macrophages were observed in a control patient. Mechanistically, the injected MSCs accumulated in the lung but not in the pancreas and strongly increased plasma exosome levels and changed plasma cytokine profiles. CONCLUSIONS/INTERPRETATION: Our results suggest that MSCs can prevent the incidence of diabetes associated with immune checkpoint cancer therapy and may be worth further consideration for new adjuvant cell therapy.


Assuntos
Diabetes Mellitus Tipo 1 , Células-Tronco Mesenquimais , Neoplasias , Animais , Anticorpos Monoclonais , Antígeno B7-H1/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Inibidores de Checkpoint Imunológico , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo
3.
Biochem Biophys Res Commun ; 614: 100-106, 2022 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-35576680

RESUMO

T-cell responses are fine-tuned by positive and negative co-signal molecules expressed on immune cells and adjacent tissues. VSIG4 is a newly identified member of the B7 family of ligands, which negatively regulates innate inflammatory and CD4+ T cell-mediated responses. However, little is known about the direct effects of VSIG4, which are exerted through an unidentified counter-receptor on CD8+ T cells. We investigated the binding of the VSIG4-Ig fusion protein during CD8+ T cell activation, and the functional involvement of VSIG4 pathway, using VSIG4-Ig and VSIG4-transfectants. VSIG4-Ig binding to CD8+ T cells was temporally observed in the CD44high phenotype during initial activation. VSIG4-Ig binding was observed earlier than the induction of PD-1, LAG3, and TIM-3, which are immune checkpoint receptors for exhausted CD8+ T cells. Immobilized VSIG4-Ig inhibited anti-CD3/CD28 mAb-induced CD8+ T cell activation, as indicated by proliferation and IFN-γ production, similar to the downregulation of T-bet and Eomesodermin transcription factors. VSIG4 on FcγR+ P815 or specific antigen-presenting E.G7 cells inhibited the generation of effector CD8+ T cells, as indicated by proliferation, IFN-γ and TNF-α expression, and granule degradation, compared to parental cells. However, the window for the regulatory function of VSIG4 was narrow and dependent on the strength of TCR (and CD28)-mediated signals. Our results suggested that VSIG4 directly delivers co-inhibitory signals via an as-yet unidentified counter-receptor on activated CD8+ T cells. VSIG4-mediated CD8+ T cell tolerance might contribute to the steady-state maintenance of homeostasis.


Assuntos
Antígenos CD28 , Linfócitos T CD8-Positivos , Animais , Antígenos CD28/genética , Interferon gama/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL
4.
Infect Immun ; 89(6)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33753411

RESUMO

Immune paralysis is a protracted state of immune suppression following the early/acute inflammatory phase of sepsis. CD11b+ Gr-1+ cells induced during sepsis are heterogeneous myeloid-derived cells (MDCs). This study investigated the contribution of MDCs to immune paralysis. Treatment of mice with zymosan (ZM) induced a marked increase in the total number of splenocytes with an increase in the proportion of Gr-1hi cells and a decrease in the proportion of T cells on day 7; levels of these cells eventually return to levels similar to those of control mice on day 21. T-cell activation and gamma interferon (IFN-γ) expression by CD8+ T cells were clearly impaired in ZM-treated mice on day 21 (d21-ZM mice). Gr-1hi cells showed a CD11b+ Ly6Ghi polymorphonuclear phenotype. Injection of lipopolysaccharide (LPS) into d21-ZM mice impaired interleukin 6 (IL-6) production in serum, accompanied by accumulation of CD11b+ Gr-1hi cells in the peripheral blood. Transfer of Gr-1hi cells from d21-ZM mice into intact mice impaired IL-6 production, but similar transfer of Gr-1hi cells from PD-1/PD-L1-deficient d21-ZM mice showed no such suppressive effect. Conversely, either depletion of Gr-1hi cells by treatment with anti-Gr-1 monoclonal antibody (MAb) or neutralization of the PD-1/PD-L1 pathway by anti-PD-1 and anti-PD-L1 MAbs during the induction phase of sepsis ameliorated ZM-induced immune suppression. Our results suggest that the PD-1/PD-L1-mediated generation of Gr-1hi cells in the early phase of sepsis is required for the late phase of immune paralysis.


Assuntos
Antígeno B7-H1/metabolismo , Imunomodulação , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Imunofenotipagem , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Sepse/etiologia , Sepse/metabolismo , Baço/citologia , Baço/imunologia , Baço/metabolismo
5.
Nat Immunol ; 10(11): 1185-92, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19783989

RESUMO

Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon laser-scanning microscopy, we show here that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen-specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. Inhibition of T cell antigen receptor (TCR)-driven stop signals depended on continued interactions between PD-1 and its ligand, PD-L1, as antibody blockade of PD-1 or PD-L1 resulted in lower T cell motility, enhanced T cell-DC contacts and caused autoimmune diabetes. Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1-PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4.


Assuntos
Antígenos de Superfície/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Antígeno B7-1/imunologia , Tolerância Imunológica , Glicoproteínas de Membrana/imunologia , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Superfície/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Antígeno B7-1/metabolismo , Antígeno B7-H1 , Antígeno CTLA-4 , Movimento Celular , Células Dendríticas/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Transplante das Ilhotas Pancreáticas , Ativação Linfocitária , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Peptídeos/metabolismo , Receptor de Morte Celular Programada 1
6.
Int Immunol ; 32(8): 509-518, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32128565

RESUMO

The sublingual mucosa (SLM) in the oral cavity is utilized as the site for sublingual immunotherapy to induce tolerance against allergens. We previously reported that CD206+ round-type macrophage-like cells were induced in the SLM after repeated antigen (e.g. cedar pollen or fluorescein isothiocyanate (FITC))-painting. In this study, we examined the phenotypic and functional properties of CD206+ cells induced by repeated FITC-painting on the SLM. CD206+ cells after the repeated FITC-painting possessed a macrophage-like CD11b+Ly6C+ F4/80+CD64+ phenotype and expressed TIM-4, which was expressed in tolerogenic tissue-resident macrophages, at a high level. SLM CD206+ cells preferentially expressed molecules related to endocytosis and homeostatic processes, including the novel B7 family of immune checkpoint molecules, as assessed by microarray analyses. SLM CD206+ cells showed preferential expression of M2-related genes such as Fizz1, Aldh1a1 and Aldh1a2 but not Ym-1 and Arginase-1. A CD206+ cell-rich status inhibited OVA-specific CD4+ T-cell responses but reciprocally enhanced the proportion of both IL-10+CD4+ cells and Foxp3+ regulatory T-cells in regional lymph nodes. Co-culture of CD206+ cells with dendritic cells (DCs) showed that IL-12 production was suppressed in DCs concurrent with the decline of the MHC class IIhiCD86+ population, which was restored by neutralization of IL-10. These results demonstrate SLM CD206+ cells show the feature of tolerogenic macrophages and down-regulate the antigen-presenting cell function of mature DCs resulting in the inhibition of CD4+ T-cell responses.


Assuntos
Alérgenos/imunologia , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Lectinas de Ligação a Manose/imunologia , Mucosa/imunologia , Receptores de Superfície Celular/imunologia , Animais , Cryptomeria/química , Feminino , Fluoresceína-5-Isotiocianato/química , Receptor de Manose , Camundongos , Camundongos Endogâmicos BALB C , Soalho Bucal/imunologia , Pólen/imunologia
7.
Biochem Biophys Res Commun ; 526(1): 218-224, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32204917

RESUMO

The immunological, and especially T cell, status of the tumor microenvironment affects tumor development and the efficacy of cancer treatment. To devise suitable combination therapies based on the results of murine tumor models, a more realistic orthotopic model is required. In this study, we generated a murine model of tongue squamous cell carcinoma (SCC), in which the tumor-immune cell interactions were recapitulated, and examined tumor- and T-cell status compared to a skin-transplanted SCC model by multiplex immunofluorescence staining for epidermal growth factor receptor, CD31, CD8, CD4, and Foxp3. Administration of SCCVII cells did not induce undesirable tissue damage or inflammation. In tongue SCC, abundant T-cell infiltration was observed at the tumor margin, but not in the core. Tongue SCC predominantly showed CD8+ T or Foxp3+ regulatory T cell (Treg)-infiltration. In contrast, skin-transplanted SCC showed abundant infiltration of T cells in the whole tumor area, which was dominated by Tregs. An orthotopic tongue SCC model showed differences in tumor and T-cell status compared to the skin-transplanted SCC model. Our tongue SCC model may enhance understanding of tumor-host interactions and enable evaluation of therapeutic efficacy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Reguladores/imunologia , Neoplasias da Língua/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Contagem de Linfócitos , Camundongos
8.
Cancer Immunol Immunother ; 69(6): 1001-1014, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32088772

RESUMO

The expression of PD-L1 on tumor cells or within the tumor microenvironment has been associated with good prognosis and sustained clinical responses in immunotherapeutic regimens based on PD-L1/PD-1/CD80 immune checkpoint blockade. To look into the current controversy in cancer immunotherapy of the relative importance of PD-L1 expression on tumor cells versus non-tumor cells of the tumor microenvironment, a hematological mouse tumor model was chosen. By combining a genetic CRISPR/Cas9 and immunotherapeutic approach and using a syngeneic hematopoietic transplantable tumor model (E.G7-cOVA tumor cells), we demonstrated that dual blockade of PD-L1 interaction with PD-1 and CD80 enhanced anti-tumor immune responses that either delayed tumor growth or led to its complete eradication. PD-L1 expression on non-tumor cells of the tumor microenvironment was required for the promotion of tumor immune escape and its blockade elicited potent anti-tumor responses to PD-L1 WT and to PD-L1-deficient tumor cells. PD-L1+ tumors implanted in PD-L1-deficient mice exhibited delayed tumor growth independently of PD-L1 blockade. These findings emphasize that PD-L1 expression on non-tumor cells plays a major role in this tumor model. These observations should turn our attention to the tumor microenvironment in hematological malignancies because of its unappreciated contribution to create a conditioned niche for the tumor to grow and evade the anti-tumor immune response.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Modelos Animais de Doenças , Humanos , Camundongos , Transfecção
9.
Odontology ; 108(2): 280-291, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31502122

RESUMO

The present study aimed to identify and compare the microbial signatures between periodontally healthy and periodontitis subjects using 454 sequences of 16S rRNA genes. Subgingival plaque samples were collected from ten periodontally healthy subjects and ten matched chronic periodontitis patients. Bacterial DNA was extracted and next-generation sequencing of 16S rRNA genes was performed. The microbial composition differed between healthy subjects and periodontitis patients at all phylogenetic levels. Particularly, 16 species, including Lautropia mirabilis and Neisseria subflava predominated in healthy subjects, whereas nine species, including Porphyromonas gingivalis and Filifactor alocis predominated in periodontitis. UniFrac, a principal coordinate and network analysis, confirmed distinct community profiles in healthy subjects and periodontitis patients. Using predicted function profiling, pathways involved in phenylpropanoid, GPI-anchor biosynthesis, and metabolism of alanine, arginine, aspartate, butanoate, cyanoamino acid, fatty acid, glutamate, methane, proline, and vitamin B6 were significantly over-represented in periodontitis patients. These results highlight the oral microbiota alterations in microbial composition in periodontitis and suggest the genes and metabolic pathways associated with health and periodontitis. Our findings help to further elucidate microbial composition and interactions in health and periodontitis.


Assuntos
Periodontite Crônica , Microbiota , Humanos , Japão , Filogenia , RNA Ribossômico 16S
10.
Br J Cancer ; 120(1): 115-127, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30382166

RESUMO

BACKGROUND: V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune-checkpoint protein. VISTA expression on tumour cells and the associated regulatory mechanisms remain unclear. We investigated VISTA expression and function in tumour cells, and evaluated its mechanism and activity. METHODS: VISTA in tumour cells was assessed by tissue microarray analysis, immunohistochemical staining and western blot. A series of in vitro assays were used to determine the function of tumour-expressed VISTA. In vivo efficacy was evaluated in syngeneic models. RESULTS: VISTA was highly expressed in human ovarian and endometrial cancers. Upregulation of VISTA in endometrial cancer was related to the methylation status of the VISTA promoter. VISTA in tumour cells suppressed T cell proliferation and cytokine production in vitro, and decreased the tumour-infiltrating CD8+ T cells in vivo. Anti-VISTA antibody prolonged the survival of tumour-bearing mice. CONCLUSIONS: This is the first demonstration that VISTA is highly expressed in human ovarian and endometrial cancer cells, and that anti-VISTA antibody treatment significantly prolongs the survival of mice bearing tumours expressing high levels of VISTA. The data suggest that VISTA is a novel immunosuppressive factor within the tumour microenvironment, as well as a new target for cancer immunotherapy.


Assuntos
Antígenos B7/genética , Neoplasias do Endométrio/genética , Neoplasias Ovarianas/genética , Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imunoterapia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
11.
Biochem Biophys Res Commun ; 518(2): 331-336, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421832

RESUMO

Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family. IL-33 and its receptor ST2 axis exert conflicting anti-tumor and pro-tumor effects in various tumors. In this study, we examined the role of endogenously produced IL-33 in the colon-26 tumor model, in which involvement of the IL-33:ST2 pathway was negligible on the tumor side. We found that the generation of regulatory T cells (Tregs) and CD8+ T cells, and IFN-γ expression by both CD4+ and CD8+ T cells (T cell activation) were impaired in IL-33-deficient mice. Overall antitumor responses, assessed by tumor growth and IFN-γ expression by tumor-infiltrating CD8+ T cells, were also impaired, even after Treg adjustment prior to tumor inoculation. These results indicate that endogenous IL-33 augmented CD8+ T cell-mediated antitumor responses in this colon carcinoma model, with higher CD8+ T cell-infiltration and overcoming pro-tumor effects by increased Tregs. Exogenous application of IL-33 into the tumors did not enhance CD8+ T cell-mediated antitumor responses despite marked elevation of innate responses showing upregulation of proinflammatory cytokine/chemokine expression, neutrophil recruitment, and dendritic cell activation. Our results suggest a dual role for endogenous IL-33 in antitumor responses and suggest that the balance of CD8+ T cells:Tregs in the tumor microenvironment is one of key factors for estimating the contribution of IL-33-mediated antitumor responses. Therefore, the development of IL-33-based cancer immunotherapy may require a target cell-specific approach.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias do Colo/imunologia , Interleucina-33/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Feminino , Técnicas de Inativação de Genes , Humanos , Interleucina-33/genética , Camundongos Endogâmicos BALB C , Camundongos Knockout
12.
Int Immunol ; 30(1): 3-11, 2018 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-29267882

RESUMO

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint receptor and ligand that regulates T-cell activation. We investigated the functional involvement of VISTA in Th2 cell-mediated immune responses using an ovalbumin (OVA)-induced allergic asthma model. Treatment with an anti-VISTA monoclonal antibody (mAb) during allergen sensitization increased the production of antibodies, including total IgE, OVA-specific IgG1 and IgG2a and allergen-specific IL-5 and IL-13; it also increased the expression of IL-13 by splenic CD4+ T cells. However, treatment with the anti-VISTA mAb during sensitization did not accelerate asthmatic responses, including airway hyper-responsiveness (AHR) or the number of eosinophils in bronchoalveolar lavage (BAL) fluid. In contrast, treatment with the anti-VISTA mAb during allergen challenge significantly augmented AHR and BAL fluid eosinophilia. This treatment also increased the production of IL-5 and IL-13 in BAL fluid and the expression of IL-13 by CD4+ T cells in draining lymph nodes. These results suggest that VISTA is involved in the regulation of Th2 cell generation and Th2 cell-mediated antibody production and regulates asthmatic responses, especially in the effector phase.


Assuntos
Alérgenos/imunologia , Proteínas de Membrana/imunologia , Células Th2/citologia , Células Th2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Reações Antígeno-Anticorpo , Asma/tratamento farmacológico , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Feminino , Citometria de Fluxo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia
13.
Adv Exp Med Biol ; 1189: 3-23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758529

RESUMO

The two-signal model of T-cell activation, proposed approximately four decades ago, has undergone various refinements while maintaining its principal doctrine. Since the discovery of CD28, a variety of co-signal molecules, including co-stimulatory and co-inhibitory receptors and ligands, have been identified. These molecules fine-tune various immune responses both in the primary or secondary lymphoid tissues and in the peripheral tissues. Most co-signal receptors are expressed and induced on T cells during distinct stages (naïve/resting, activating, memory, and exhausting). These co-signaling pathways play critical and diverse roles in maintaining T-cell tolerance and eliciting T-cell immune responses in health and disease. This introductory chapter provides a historical overview of the key findings that have led to our current view of T-cell co-stimulation.


Assuntos
Antígenos CD28/metabolismo , Ativação Linfocitária , Transdução de Sinais , Linfócitos T/citologia , Humanos , Tolerância Imunológica
14.
Adv Exp Med Biol ; 1189: 25-51, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758530

RESUMO

Immune responses are controlled by the optimal balance between protective immunity and immune tolerance. T-cell receptor (TCR) signals are modulated by co-signaling molecules, which are divided into co-stimulatory and co-inhibitory molecules. By expression at the appropriate time and location, co-signaling molecules positively and negatively control T-cell differentiation and function. For example, ligation of the CD28 on T cells provides a critical secondary signal along with TCR ligation for naive T-cell activation. In contrast, co-inhibitory signaling by the CD28-B7 family is important to regulate immune homeostasis and host defense, as these signals limit the strength and duration of immune responses to prevent autoimmunity. At the same time, microorganisms or tumor cells can use these pathways to establish an immunosuppressive environment to inhibit the immune responses against themselves. Understanding these co-inhibitory pathways will support the development of new immunotherapy for the treatment of tumors and autoimmune and infectious diseases. Here, we introduce diverse molecules belonging to the members of the CD28-B7 family.


Assuntos
Antígeno B7-1/metabolismo , Antígenos CD28/metabolismo , Ativação Linfocitária , Transdução de Sinais , Linfócitos T/citologia , Humanos , Tolerância Imunológica , Imunoterapia
15.
Clin Oral Investig ; 23(3): 1489-1493, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30680442

RESUMO

OBJECTIVES: This study aimed to define the comprehensive bacterial flora of the healthy oral cavity by identifying and comparing bacterial species in different subgingival sites using 454 sequencing of 16S rRNA genes. MATERIALS AND METHODS: Subgingival plaque samples were taken from six target teeth (central incisor, first premolar, and first molar in both the maxilla and mandible) of 10 periodontally healthy patients. Bacterial DNA was extracted and next-generation sequencing of 16S rRNA genes was performed. RESULTS: Bacterial composition in phylum level was similar for all sites within the same individual irrespective of tooth location. Unweighted UniFrac distance values of microbiome also showed that average distance was significantly larger between subjects than between tooth locations of the same subjects. CONCLUSIONS: The present results clarify the lack of effect of tooth location in the healthy subgingival microbiota. Results may suggest that any subgingival site can demonstrate similar subject-specific microbiota. CLINICAL RELEVANCE: This investigation offers a better understanding of the uniqueness of the oral microbiome. The present study will facilitate sampling in future subgingival microbiological studies.


Assuntos
Bactérias/classificação , Gengiva/microbiologia , Microbiota , DNA Bacteriano , Voluntários Saudáveis , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , RNA Ribossômico 16S/genética
16.
Immunology ; 152(3): 507-516, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28685820

RESUMO

Interleukin 27 (IL-27) has been identified as a potent cytokine in the differentiation of type 1 regulatory T (Tr1) cells through interactions with several key elements, including transcription factors such as aryl hydrocarbon receptor and IL-21. Autocrine production of IL-21 is known to be important for maintaining IL-10 expression by Tr1 cells. Although previous studies have shown that the phosphoinositide 3-kinase (PI3K) -Akt axis contributes to the differentiation of helper T-cell subsets, the role of the PI3K pathway on Tr1 cell differentiation remains to be elucidated. Here, we demonstrate that suppression of the PI3K-Akt pathway results in impairment of IL-27-induced Tr1 (IL-27-Tr1) cell differentiation in vitro and in vivo. Furthermore, this suppression down-regulates IL-21 receptor expression by Tr1 cells, followed by suppression of IL-10 expression by IL-27-Tr1 cells. These results suggest that the PI3K pathway enhances IL-10 expression by IL-27-Tr1 cells through up-regulation of IL-21 receptors.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Interleucina-27/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Células Cultivadas , Feminino , Proteína Forkhead Box O1/imunologia , Proteína Forkhead Box O1/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Genótipo , Interleucina-10/genética , Interleucina-10/metabolismo , Subunidade alfa de Receptor de Interleucina-21/imunologia , Subunidade alfa de Receptor de Interleucina-21/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
17.
Immunology ; 151(2): 248-260, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28211040

RESUMO

T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T-cell receptor complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti-CD3 treatment on green fluorescent protein (GFP)+ islet-specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time-points during treatment to assess cell presence in various organs as well as gene expression and cytokine production. We find, in this model, that anti-CD3 treatment does not preferentially deplete the transferred effector cells, but instead inhibits their metabolic function and their production of interferon-γ. Programmed cell death protein 1 (PD-1) expression was up-regulated on the effector cells from anti-CD3-treated mice, and diabetes induced through anti-PD-L1 antibody could only be reversed with anti-CD3 antibody if the anti-CD3 treatment lasted beyond the point when the anti-PD-L1 antibody was washed out of the system. This suggests that PD-1/PD-L1 interaction plays an important role in the anti-CD3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti-CD3 therapy can reverse diabetogenesis.


Assuntos
Anticorpos/imunologia , Complexo CD3/imunologia , Inflamação/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Regulação para Cima , Animais , Feminino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia
18.
Biochem Biophys Res Commun ; 490(4): 1294-1300, 2017 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-28687491

RESUMO

Contact allergy is a T cell-mediated, delayed-type hypersensitivity generated by contact exposure of an allergen to the skin and mucosal surface. The clinical manifestations of allergic responses between the skin and oral mucosa vary and the differences in immunopathology have not been clarified. We generated hapten-induced contact hypersensitivity (CH) of the buccal mucosa (BM) in parallel studies with ear skin (ES) CH, and observed several characteristic findings of BM CH. The BM challenge induced more rapid and more severe inflammation than the ES challenge, with abundant granulocyte and CD8+ T cell infiltration. However, these inflammatory responses diminished quickly. Recruiting CD8+ T cells in the BM had higher ratios of CD62L-CD44low-hi memory-type cells, and showed impaired IFN-γ, greater PD-1, and comparable Ki-67 expression, suggesting that the recruiting-proliferating CD8+ T cells were unable to differentiate into effector T cells and converted into exhausted T cells at the local site. This finding may explain the rapid recovery of the BM from severe inflammation. Preferentially greater expression of PD-1 ligand (B7-H1), was observed in the BM epithelium under the peak inflammation, and the absence of B7-H1 further accelerated CH responses, suggesting the occurrence of PD-1:B7-H1-mediated immune regulation at the local site. Our results may facilitate the understanding of the unique features of contact allergies in the oral mucosa, and guide the development of new strategies for control of contact allergy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Dermatite de Contato/imunologia , Granulócitos/imunologia , Mucosa Bucal/imunologia , Pele/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/patologia , Dermatite de Contato/etiologia , Dermatite de Contato/genética , Dermatite de Contato/patologia , Dinitrofluorbenzeno/toxicidade , Orelha , Feminino , Regulação da Expressão Gênica , Granulócitos/efeitos dos fármacos , Granulócitos/patologia , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/imunologia , Memória Imunológica , Imunofenotipagem , Interferon gama/genética , Interferon gama/imunologia , Antígeno Ki-67/genética , Antígeno Ki-67/imunologia , Selectina L/genética , Selectina L/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia , Especificidade de Órgãos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/patologia
19.
J Hepatol ; 64(6): 1327-38, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26924452

RESUMO

BACKGROUND & AIMS: Acute hepatitis is often mediated by cytotoxic T lymphocytes (CTLs); however, the intrinsic parameters that limit CTL-mediated liver injury are not well understood. METHODS: To investigate whether acute liver damage is limited by molecules that decrease the lifespan or effector function of CTLs, we used a well-characterized transgenic (Tg) mouse model in which acute liver damage develops upon transfer of T cell receptor (TCR) Tg CD8 T cells. Recipient Tg mice received donor TCR Tg T cells deficient for either the pro-apoptotic molecule Bim, which regulates CTL survival, or suppressor of cytokine signaling-1 (SOCS-1), which controls expression of common gamma chain cytokines; the effects of anti-PD-L1 neutralizing antibodies were also assessed. RESULTS: Use of Bim-deficient donor T cells and/or PD-L1 blockade increased the number of intrahepatic T cells without affecting the degree and kinetic of acute hepatitis. In contrast, SOCS-1-deficient T cells induced a heightened, prolonged acute hepatitis caused by their enhanced cytotoxic function and increased expansion. Although they inflicted more severe acute liver damage, SOCS-1-deficient T cells never precipitated chronic hepatitis and became exhausted. CONCLUSIONS: The degree of acute hepatitis is regulated by the function of CD8 T cells, but is not affected by changes in CTL lifespan. Although manipulation of the examined parameters affected acute hepatitis, persistent hepatitis did not ensue, indicating that, in the presence of high intrahepatic antigen load, changes in these factors in isolation were not sufficient to prevent T cell exhaustion and mediate progression to chronic hepatitis.


Assuntos
Hepatite/etiologia , Linfócitos T Citotóxicos/imunologia , Doença Aguda , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/fisiologia , Proteína 11 Semelhante a Bcl-2/fisiologia , Sobrevivência Celular , Hepatite/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Proteína 1 Supressora da Sinalização de Citocina/fisiologia , Linfócitos T Citotóxicos/fisiologia
20.
Eur J Immunol ; 45(4): 1019-29, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25630305

RESUMO

Studies examining the role of PD-1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD-1/PD-L1 has distinct influences on different CD4(+) T-cell subsets. PD-1/PD-L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2-type immune response, but by allowing the development of a concomitant Th17-type immune response. Supporting differential CD4(+) T-cell responsiveness to PD-1-mediated inhibition, naïve PD-1(-/-) mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD-1 in WT cells limited cytokine production by in vitro polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro polarized Th2 cells. Furthermore, PD-1 ligation enhanced Th2 cytokine production by naïve T cells cultured under nonpolarizing conditions. These data demonstrate that different CD4(+) T-cell subsets respond differentially to PD-1 ligation and may explain some of the variable results observed in control of allergic asthma by the PD-1 family members. As the PD-1/PD-L1 axis limits asthma severity by constraining Th17 cell activity, this suggests that severe allergic asthma may be associated with a defective PD-1/PD-L1 regulatory axis in some individuals.


Assuntos
Asma/imunologia , Antígeno B7-H1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Células Th17/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Cultivadas , Citocinas/biossíntese , Modelos Animais de Doenças , Interleucina-12/sangue , Pulmão/citologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 2 Ligante de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Pyroglyphidae/imunologia , Baço/citologia , Subpopulações de Linfócitos T/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th17/citologia , Células Th2/citologia , Células Th2/imunologia
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