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1.
Nat Immunol ; 18(9): 1046-1057, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28714979

RESUMO

Translation is a critical process in protein synthesis, but translational regulation in antigen-specific T cells in vivo has not been well defined. Here we have characterized the translatome of virus-specific CD8+ effector T cells (Teff cells) during acute infection of mice with lymphocytic choriomeningitis virus (LCMV). Antigen-specific T cells exerted dynamic translational control of gene expression that correlated with cell proliferation and stimulation via the T cell antigen receptor (TCR). The translation of mRNAs that encode translation machinery, including ribosomal proteins, was upregulated during the T cell clonal-expansion phase, followed by inhibition of the translation of those transcripts when the CD8+ Teff cells stopped dividing just before the contraction phase. That translational suppression was more pronounced in terminal effector cells than in memory precursor cells and was regulated by antigenic stimulation and signals from the kinase mTOR. Our studies show that translation of transcripts encoding ribosomal proteins is regulated during the differentiation of CD8+ Teff cells and might have a role in fate 'decisions' involved in the formation of memory cells.


Assuntos
Infecções por Arenaviridae/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Biossíntese de Proteínas/imunologia , Animais , Infecções por Arenaviridae/genética , Infecções por Arenaviridae/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Citometria de Fluxo , Regulação da Expressão Gênica , Memória Imunológica/imunologia , Interferon gama/imunologia , Vírus da Coriomeningite Linfocítica , Camundongos , Biossíntese de Proteínas/genética , RNA Mensageiro/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/imunologia
2.
Arthritis Rheumatol ; 67(3): 773-84, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25385309

RESUMO

OBJECTIVE: Follicular helper T (Tfh) cells are critical for the development of protective antibodies via germinal center (GC) B cell responses; however, uncontrolled Tfh cell expansion activates autoreactive B cells to produce antibodies that cause autoimmunity. The mechanisms that control Tfh cell homeostasis remain largely unknown. The aim of this study was to determine the contribution of BAFF to Tfh cell responses in autoimmunity. METHODS: We analyzed the properties of Tfh cells in lupus-prone mice sufficient or deficient in BCMA. Adoptive transfer studies and mixed bone marrow chimeras were used to test BCMA signaling in T cells. We assessed BAFF stimulation of Tfh cells through in vitro cell cocultures and in vivo depletion studies using flow cytometry. RESULTS: In Nba2 mice, Tfh cells expressed the BAFF receptors BCMA and B lymphocyte stimulator receptor 3 (BR-3) and accumulated in the spleen when BCMA was absent. BCMA deficiency in T cells promoted the expansion of Tfh cells, GC formation, autoantibody production, and interferon-γ (IFNγ) production by Tfh cells through BR-3. IFNγ-producing Tfh cells increased BAFF expression in dendritic cells. Blocking BAFF or IFNγ in vivo reduced Tfh cell accumulation and reduced autoimmunity in BCMA-deficient animals. Moreover, circulating Tfh-like cells that expressed BR-3 (but not BCMA) were elevated in patients with systemic lupus erythematosus, and this correlated with serum BAFF and IFNγ levels. CONCLUSION: In Nba2 mice, BCMA negatively regulates Tfh cell expansion, while BAFF signaling through BR-3 promotes Tfh cell accumulation. Our findings suggest that the balance between BCMA and BR-3 signaling in Tfh cells serves as a checkpoint of immune tolerance.


Assuntos
Autoimunidade/imunologia , Fator Ativador de Células B/fisiologia , Interferon gama/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Animais , Receptor do Fator Ativador de Células B/metabolismo , Antígeno de Maturação de Linfócitos B/metabolismo , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Terpenos/farmacologia
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