RESUMO
The active ubiquitin E3 ligase GRAIL is crucial in the induction of CD4 T cell anergy. Here we show that GRAIL is associated with and regulated by two isoforms of the ubiquitin-specific protease otubain 1. In lethally irradiated mice reconstituted with bone marrow cells from T cell receptor-transgenic mice retrovirally transduced to express the genes encoding these proteases, otubain 1-expressing cells contained negligible amounts of endogenous GRAIL, proliferated well and produced large amounts of interleukin 2 after antigenic stimulation. In contrast, cells expressing the alternatively spliced isoform, otubain 1 alternative reading frame 1, contained large amounts of endogenous GRAIL and were functionally anergic, and they proliferated poorly and produced undetectable interleukin 2 when stimulated in a similar way. Thus, these two proteins have opposing epistatic functions in controlling the stability of GRAIL expression and the resultant anergy phenotype in T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Anergia Clonal/imunologia , Endopeptidases/imunologia , Ubiquitina-Proteína Ligases/imunologia , Ubiquitina/imunologia , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sequência de Bases , Linfócitos T CD4-Positivos/citologia , Divisão Celular/imunologia , Humanos , Isoenzimas/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Dados de Sequência Molecular , Alinhamento de Sequência , Técnicas do Sistema de Duplo-Híbrido , Proteases Específicas de UbiquitinaRESUMO
Chemokine receptors play an important role in the trafficking of various immune cell types to sites of inflammation. Several chemokine receptors are differentially expressed in Th1 and Th2 effector populations. Th2 cells selectively express CCR3, CCR4, and CCR8, which could direct their trafficking to sites of allergic inflammation. Additionally, increased expression of the CCR8 ligand, TCA-3, has been detected in affected lungs in a mouse model of asthma. In this study, CCR8-deficient mice were generated to address the biological role of CCR8 in a model of allergic airway disease. Using two different protocols of allergen challenge, we demonstrate that absence of CCR8 does not affect the development of pulmonary eosinophilia and Th2 cytokine responses. In addition, administration of anti-TCA-3-neutralizing Ab during allergen sensitization and rechallenge failed to inhibit airway allergic inflammation. These results suggest that CCR8 does not play an essential role in the pathogenesis of inflammation in this mouse model of allergic airway disease.
Assuntos
Quimiocinas CC/metabolismo , Modelos Animais de Doenças , Receptores de Quimiocinas/fisiologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Antígenos/administração & dosagem , Antígenos/imunologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Inibição de Migração Celular , Quimiocina CCL1 , Cruzamentos Genéticos , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Relação Dose-Resposta Imunológica , Esquema de Medicação , Feminino , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptores CCR8 , Receptores de Quimiocinas/biossíntese , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Hipersensibilidade Respiratória/genéticaRESUMO
Using a genome-scale approach to study transcription levels in a human CD8+ T-cell clone, a recent study has suggested that the repertoire of molecules on the surface of T cells is close to being completely characterized.
