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1.
PLoS One ; 7(1): e29355, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22272233

RESUMO

BACKGROUND: Upon antigen exposure, cord blood derived T cells respond to ubiquitous environmental antigens by high proliferation. To date it remains unclear whether these "excessive" responses relate to different regulatory properties of the putative T regulatory cell (Treg) compartment or even expansion of the Treg compartment itself. METHODS: Cord blood (>37 week of gestation) and peripheral blood (healthy controls) were obtained and different Treg cell subsets were isolated. The suppressive potential of Treg populations after antigen exposure was evaluated via functional inhibition assays ([(3)H]thymidine incorporation assay and CFSE staining) with or without allergen stimulation. The frequency and markers of CD4(+)CD25(high)FoxP3(+) T cells were characterized by mRNA analysis and flow cytometry. RESULTS: Cord blood derived CD4(+)CD25(high) cells did not show substantial suppressor capacity upon TCR activation, in contrast to CD4(+)CD25(high) cells freshly purified from adult blood. This could not be explained by a lower frequency of FoxP3(+)CD4(+)CD25(high)cells or FOXP3 mRNA expression. However, after antigen-specific stimulation in vitro, these cells showed strong proliferation and expansion and gained potent suppressive properties. The efficiency of their suppressive capacity can be enhanced in the presence of endotoxins. If T-cells were sorted according to their CD127 expression, a tiny subset of Treg cells (CD4(+)CD25(+)CD127(low)) is highly suppressive even without prior antigen exposure. CONCLUSION: Cord blood harbors a very small subset of CD4(+)CD25(high) Treg cells that requires antigen-stimulation to show expansion and become functional suppressive Tregs.


Assuntos
Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Sangue Fetal/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Células Cultivadas , Sangue Fetal/imunologia , Sangue Fetal/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica , Humanos , Recém-Nascido , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Lactoglobulinas/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
2.
J Allergy Clin Immunol ; 127(3): 701-21.e1-70, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21377040

RESUMO

Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among T(h) and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections.


Assuntos
Doenças do Sistema Imunitário , Interferon gama/fisiologia , Interleucinas/imunologia , Receptores de Interferon/imunologia , Receptores de Interleucina/imunologia , Animais , Humanos , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/imunologia , Interleucinas/classificação , Camundongos
3.
J Exp Med ; 206(12): 2701-15, 2009 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-19917773

RESUMO

Forkhead box P3 (FOXP3)(+)CD4(+)CD25(+) inducible regulatory T (iT reg) cells play an important role in immune tolerance and homeostasis. In this study, we show that the transforming growth factor-beta (TGF-beta) induces the expression of the Runt-related transcription factors RUNX1 and RUNX3 in CD4(+) T cells. This induction seems to be a prerequisite for the binding of RUNX1 and RUNX3 to three putative RUNX binding sites in the FOXP3 promoter. Inactivation of the gene encoding RUNX cofactor core-binding factor-beta (CBFbeta) in mice and small interfering RNA (siRNA)-mediated suppression of RUNX1 and RUNX3 in human T cells resulted in reduced expression of Foxp3. The in vivo conversion of naive CD4(+) T cells into Foxp3(+) iT reg cells was significantly decreased in adoptively transferred Cbfb(F/F) CD4-cre naive T cells into Rag2(-/-) mice. Both RUNX1 and RUNX3 siRNA silenced human T reg cells and Cbfb(F/F) CD4-cre mouse T reg cells showed diminished suppressive function in vitro. Circulating human CD4(+) CD25(high) CD127(-) T reg cells significantly expressed higher levels of RUNX3, FOXP3, and TGF-beta mRNA compared with CD4(+)CD25(-) cells. Furthermore, FOXP3 and RUNX3 were colocalized in human tonsil T reg cells. These data demonstrate Runx transcription factors as a molecular link in TGF-beta-induced Foxp3 expression in iT reg cell differentiation and function.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Fatores de Transcrição Forkhead/imunologia , Tolerância Imunológica/fisiologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/imunologia , Fatores de Transcrição Forkhead/genética , Inativação Gênica , Humanos , Camundongos , Camundongos Knockout , Tonsila Palatina/imunologia , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/imunologia , RNA Interferente Pequeno , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia
4.
J Allergy Clin Immunol ; 124(1): 74-80.e1-8, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19523671

RESUMO

BACKGROUND: T-cell infiltration of submucosa, release of proinflammatory cytokines leading to epithelial activation, and contributions to inflammation are observed in chronic rhinosinusitis (CRS). OBJECTIVES: Molecular mechanisms and kinetics of T-cell interaction with sinus epithelium leading to activation followed by subsequent apoptosis of epithelial cells were the focus of the current study. METHODS: Primary human sinus epithelial cells and T cells generated from sinus tissues of healthy individuals and patients with CRS with or without allergy and sinus tissue biopsies were characterized in terms of activation (surface marker expression, cytokine production via real-time PCR, confocal microscopy, ELISA) and apoptosis (annexin V/7-amino-actinomycin D staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, receptor expression by flow cytometry, confocal microscopy) of epithelial cells. RESULTS: Primary human sinus epithelial cells isolated from patients with CRS were at an activated state with upregulated expression of HLA-DR, IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and TNF-related apoptosis-inducing ligand (TRAIL) compared with healthy individuals. The expressions of these chemokines, HLA-DR, TRAIL, and TNF receptor 2 were significantly induced by IFN-gamma, whereas TRAIL receptor 4 was downregulated. Epithelial cells started to undergo apoptosis 48 hours after IFN-gamma stimulation when the transcription of proinflammatory cytokines and chemokines decreased to initial levels. The essential factors for sinus epithelial apoptosis were T(H)1 cells and IFN-gamma. Epithelial apoptosis was enhanced by Fas-Fas-ligand and TRAIL-TRAIL receptor 2 interactions. Remarkable apoptosis of epithelial cells and shedding was observed in CRS in situ. CONCLUSION: Epithelial cell interaction with activated T cells is a biphasic phenomenon in CRS. Initially activated T cells lead to activation and induction of proinflammatory functions of epithelial cells, and thereafter their apoptotic death, resulting in no more contribution to inflammation, takes place.


Assuntos
Células Epiteliais/imunologia , Rinite/imunologia , Sinusite/imunologia , Linfócitos T/imunologia , Apoptose , Células Cultivadas , Quimiocinas/metabolismo , Doença Crônica , Citocinas/metabolismo , Células Epiteliais/citologia , Humanos , Imuno-Histoquímica , Interferon gama/metabolismo , Seios Paranasais/citologia , Seios Paranasais/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
J Exp Med ; 205(12): 2887-98, 2008 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-19001136

RESUMO

High dose bee venom exposure in beekeepers by natural bee stings represents a model to understand mechanisms of T cell tolerance to allergens in healthy individuals. Continuous exposure of nonallergic beekeepers to high doses of bee venom antigens induces diminished T cell-related cutaneous late-phase swelling to bee stings in parallel with suppressed allergen-specific T cell proliferation and T helper type 1 (Th1) and Th2 cytokine secretion. After multiple bee stings, venom antigen-specific Th1 and Th2 cells show a switch toward interleukin (IL) 10-secreting type 1 T regulatory (Tr1) cells. T cell regulation continues as long as antigen exposure persists and returns to initial levels within 2 to 3 mo after bee stings. Histamine receptor 2 up-regulated on specific Th2 cells displays a dual effect by directly suppressing allergen-stimulated T cells and increasing IL-10 production. In addition, cytotoxic T lymphocyte-associated antigen 4 and programmed death 1 play roles in allergen-specific T cell suppression. In contrast to its role in mucosal allergen tolerance, transforming growth factor beta does not seem to be an essential player in skin-related allergen tolerance. Thus, rapid switch and expansion of IL-10-producing Tr1 cells and the use of multiple suppressive factors represent essential mechanisms in immune tolerance to a high dose of allergens in nonallergic individuals.


Assuntos
Alérgenos , Venenos de Abelha , Abelhas , Tolerância Imunológica/fisiologia , Interleucina-10/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores , Adulto , Idoso , Alérgenos/administração & dosagem , Alérgenos/imunologia , Animais , Venenos de Abelha/administração & dosagem , Venenos de Abelha/imunologia , Citocinas/sangue , Citocinas/genética , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional , Ocupações , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores Histamínicos/genética , Receptores Histamínicos/imunologia , Estações do Ano , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
6.
J Allergy Clin Immunol ; 120(3): 688-95, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17631952

RESUMO

BACKGROUND: The combination of anti-IgE (omalizumab) therapy with ragweed injection immunotherapy for seasonal allergic rhinitis results in a significant reduction in systemic side effects and enhanced efficacy compared with immunotherapy alone. One proposed mechanism of immunotherapy is to induce regulatory antibodies that inhibit facilitated antigen presentation. OBJECTIVES: We sought to determine whether the combination protocol has a cumulative effect on inhibition of facilitated antigen presentation both during and after discontinuation of treatment. METHODS: Ragweed allergen immunotherapy with and without omalizumab therapy was tested in a 4-arm, double-blind, placebo-controlled study. Flow cytometry was used to detect serum inhibitory activity for IgE-facilitated CD23-dependent allergen binding to B cells as a surrogate marker for facilitated antigen presentation. Serum ragweed-specific IgG4 was measured by means of ELISA. RESULTS: Immunotherapy alone resulted in partial inhibition of allergen-IgE binding after 5 to 19 weeks of treatment compared with baseline (P < .01). Complete inhibition of allergen-specific IgE binding was observed in both treatment groups receiving omalizumab (P < .001). Allergen-specific IgG4 levels were only increased after immunotherapy (P < .05), both in the presence and absence of anti-IgE treatment. Combined treatment resulted in the induction of long-lasting inhibitory antibody function for up to 42 weeks compared with either treatment alone. CONCLUSION: Ragweed immunotherapy induced serum regulatory antibodies that partially blocked binding of allergen-IgE complexes to B cells. Additional treatment with anti-IgE, by directly blocking IgE binding to CD23, completely inhibited allergen-IgE binding. CLINICAL IMPLICATIONS: The combination of ragweed immunotherapy and anti-IgE resulted in prolonged inhibition of allergen-IgE binding compared with either treatment alone, events that might contribute to enhanced efficacy.


Assuntos
Antialérgicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Dessensibilização Imunológica , Imunoglobulina E/efeitos dos fármacos , Rinite Alérgica Sazonal/terapia , Adulto , Ambrosia/imunologia , Anticorpos Anti-Idiotípicos , Anticorpos Monoclonais Humanizados , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/imunologia , Antígenos de Plantas/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Terapia Combinada , Método Duplo-Cego , Citometria de Fluxo , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Fragmentos Fab das Imunoglobulinas/imunologia , Pessoa de Meia-Idade , Omalizumab
7.
Eur J Immunol ; 33(10): 2717-26, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14515255

RESUMO

In allergy and asthma, the fine balance between the T helper (Th) 1, Th2 and T regulatory cytokine responses appears to be shifted towards Th2. Here, we report that synthetic lipopeptides which contain the typical lipid part of the lipoprotein of gram-negative bacteria stimulate a distinct regulatory cytokine pattern and inhibit several Th2 cell-related phenomena. The most potent analogue of synthetic lipopeptides, lipopeptide CGP 40774 (LP40) was not active in MyD88-deficient mice and stimulated Toll-like receptor (TLR)-2, but not TLR-4. LP40 potentiated the production of IFN-gamma and IL-10, but not IL-4 and IL-5 by human T cells. In addition, triggering of TLR-2 by lipopeptides promoted the in vitro differentiation of naive T cells towards IL-10- and IFN-gamma-producing T cells and suppressed IL-4 production by Th2 cells. Accordingly, LP40 inhibited IgE production induced by allergen, anti-IgD antibody, Nippostrongylus brasiliensis or murine acquired immunodeficiency virus. Furthermore, ovalbumin-induced lung eosinophilic inflammation was abolished and Schistosoma mansoni egg-induced granuloma size and eosinophil counts were suppressed in mice by LP40. These results demonstrate that stimulation of TLR-2 by lipopeptides represents a novel way for possible treatment of allergy and asthma by regulating the disrupted cytokine balance.


Assuntos
Antialérgicos/farmacologia , Eosinofilia/prevenção & controle , Imunoglobulina E/biossíntese , Lipoproteínas/farmacologia , Células Th2/efeitos dos fármacos , Alérgenos/imunologia , Animais , Feminino , Humanos , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucina-12/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Schistosoma mansoni/imunologia , Células Th2/imunologia
8.
J Immunol ; 171(2): 1078-84, 2003 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-12847282

RESUMO

Activation and skin-selective homing of T cells and their effector functions in the skin represent sequential immunological events in the pathogenesis of atopic dermatitis (AD). Apoptosis of keratinocytes, induced mainly by T cells and mediated by IFN-gamma and Fas, is the essential pathogenetic event in eczema formation. Keratinocyte apoptosis appears as activation-induced cell death in AD. By IFN-gamma stimulation, chemokines such as IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant are strongly up-regulated in keratinocytes. These chemokines attract T cells bearing the specific receptor CXCR3, which is highly expressed on T cells isolated from skin biopsies of AD patients. Accordingly, an increased T cell chemotaxis was observed toward IFN-gamma-treated keratinocytes. Supporting these findings, enhanced IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant expression was observed in lesional AD skin by immunohistochemical staining. These results indicate a second step of chemotaxis inside the skin after transendothelial migration of the inflammatory cells. Keratinocytes undergoing apoptosis in acute eczematous lesions release chemokines that attract more T cells toward the epidermis, which may further augment the inflammation and keratinocyte apoptosis.


Assuntos
Apoptose/imunologia , Movimento Celular/imunologia , Quimiocinas CXC/metabolismo , Quimiotaxia de Leucócito/imunologia , Dermatite Atópica/imunologia , Endotélio/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Queratinócitos/metabolismo , Subpopulações de Linfócitos T/patologia , Adulto , Idoso , Linhagem Celular , Células Cultivadas , Quimiocina CXCL10 , Quimiocina CXCL11 , Quimiocina CXCL9 , Quimiocinas CXC/biossíntese , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Endotélio/citologia , Endotélio/imunologia , Epiderme/imunologia , Epiderme/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Interferon gama/farmacologia , Queratinócitos/citologia , Queratinócitos/imunologia , Pessoa de Meia-Idade , Receptores CXCR3 , Receptores de Quimiocinas/biossíntese , Subpopulações de Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/imunologia
9.
FASEB J ; 17(9): 1026-35, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12773485

RESUMO

T cells constitute a large population of cellular infiltrate in atopic/allergic inflammation and a dysregulated, Th2-biased peripheral immune response appears to be an important pathogenetic factor. In atopic dermatitis, circulating cutaneous lymphocyte-associated antigen-bearing (CLA+) CD45RO+ T cells with skin-specific homing property represent an activated memory/effector T cell subset. They express high levels of Fas and Fas ligand and undergo activation-induced apoptosis. The freshly purified CLA+ CD45RO+ T cells of atopic individuals display distinct features of in vivo-triggered apoptosis such as pro-caspase degradation and active caspase-8 formation. In particular, the Th1 compartment of activated memory/effector T cells selectively undergoes activation-induced cell death, skewing the immune response toward surviving Th2 cells in atopic dermatitis patients. The apoptosis of circulating memory/effector T cells was confined to atopic individuals whereas non-atopic patients such as psoriasis, intrinsic-type asthma, contact dermatitis, intrinsic type of atopic dermatitis, bee venom allergic patients, and healthy controls showed no evidence for enhanced T cell apoptosis in vivo. These results define a novel mechanism for peripheral Th2 response in atopic diseases.


Assuntos
Apoptose , Dermatite Atópica/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adulto , Antígenos de Diferenciação de Linfócitos T , Antígenos de Neoplasias , Células Clonais , Citocinas/biossíntese , Dermatite Atópica/patologia , Proteína Ligante Fas , Humanos , Memória Imunológica , Antígenos Comuns de Leucócito/análise , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/metabolismo , Subpopulações de Linfócitos T/classificação , Receptor fas/metabolismo
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