RESUMO
Previous studies have indicated that the E2A gene products are required to initiate B lineage development. Here, we demonstrate that E2A(+/-) B cells that express an autoreactive B cell receptor fail to mature due in part to an inability to activate secondary immunoglobulin (Ig) light chain gene rearrangement. Both RAG1/2 gene expression and RS deletion are severely defective in E2A(+/-) mice. Additionally, we demonstrate that E2A(+/-) mice show an increase in the proportion of marginal zone B cells with a concomitant decrease in the proportion of follicular B cells. In contrast, Id3-deficient splenocytes show a decline in the proportion of marginal zone B cells. Based on these observations, we propose that E-protein activity regulates secondary Ig gene rearrangement at the immature B cell stage and contributes to cell fate determination of marginal zone B cells. Additionally, we propose a model in which E-proteins enforce the developmental checkpoint at the immature B cell stage.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteínas de Ligação a DNA/metabolismo , Edição de RNA , Receptores de Antígenos de Linfócitos B/genética , Fatores de Transcrição/metabolismo , Animais , Linfócitos B/citologia , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Primers do DNA/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Expressão Gênica , Rearranjo Gênico de Cadeia Leve de Linfócito B , Genes RAG-1 , Sequências Hélice-Alça-Hélice , Heterozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fatores de Transcrição TCF , Proteína 1 Semelhante ao Fator 7 de Transcrição , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
Activated mature B cells in which the DNA-binding activity of E-proteins has been disrupted fail to undergo class switch recombination. Here we show that activated B cells overexpressing the antagonist helix-loop-helix protein Id3 do not induce expression of the murine Aicda gene encoding activation-induced deaminase (AID). A highly conserved intronic regulatory element in Aicda binds E-proteins both in vitro and in vivo. The transcriptional activity of this element is regulated by E-proteins. We show that the enforced expression of AID in cells overexpressing Id3 partially restores class switch recombination. Taken together, our observations link helix-loop-helix activity and Aicda gene expression in a common pathway, in which E-protein activity is required for the efficient induction of Aicda transcription.
Assuntos
Linfócitos B/imunologia , Citidina Desaminase/biossíntese , Proteínas de Ligação a DNA/imunologia , Regulação Enzimológica da Expressão Gênica/imunologia , Fatores de Transcrição/imunologia , Animais , Linfócitos B/metabolismo , Sequência de Bases , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/imunologia , Ativação Enzimática , Feminino , Sequências Hélice-Alça-Hélice/imunologia , Switching de Imunoglobulina/imunologia , Isotipos de Imunoglobulinas/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Transdução de Sinais/imunologia , Fatores de Transcrição TCF , Proteína 1 Semelhante ao Fator 7 de Transcrição , Fatores de Transcrição/genéticaRESUMO
Lymphocytes arise from hematopoietic stem cells through the coordinated action of transcription factors. The E proteins (E12, E47, HEB and E2-2) have emerged as key regulators of both B and T lymphocyte differentiation. This review summarizes the current data and examines the various functions of E proteins and their antagonists, Id2 and Id3, throughout lymphoid maturation. Beyond an established role in B and T lineage commitment, E proteins continue to be essential at subsequent stages of development. E protein activity regulates the expression of surrogate and antigen receptor genes, promotes Ig and TCR rearrangements, and coordinates cell survival and proliferation with developmental progression in response to TCR signaling. Finally, this review also discusses the role of E47 as a tumor suppressor.
