RESUMO
Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II-restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Proteínas do Leite , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Transativadores/fisiologia , Animais , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Fator de Transcrição STAT3 , Fator de Transcrição STAT5RESUMO
Cytokine signals are known to contribute to CD8+ memory T cell homeostasis, but an exact understanding of the mechanism(s) has remained elusive. We have now investigated the role of Stat5 proteins in this process. Whereas Stat5a and Stat5b KO mice have decreased numbers of CD8+ T cells, Stat5-transgenic mice have an increased number of these cells. Stat5b-transgenic mice exhibit increased Ag-induced cell death of CD4+ T cells and augmented proliferation and Bcl-2 expression in CD8+ T cells, providing a basis for this finding. Moreover, CD8+ memory T cells are substantially affected by Stat5 levels. These findings identify Stat5 proteins as critical signaling mediators used by cytokines to regulate CD8+ T cell homeostasis.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Ligação a DNA/fisiologia , Homeostase/imunologia , Proteínas do Leite , Transdução de Sinais/imunologia , Transativadores/fisiologia , Animais , Relação CD4-CD8 , Linfócitos T CD8-Positivos/metabolismo , Divisão Celular/genética , Divisão Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Quimiocina CCL5/biossíntese , Cruzamentos Genéticos , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Homeostase/genética , Interferon gama/biossíntese , Subunidade gama Comum de Receptores de Interleucina , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Interleucina-7/deficiência , Receptores de Interleucina-7/genética , Fator de Transcrição STAT5 , Transdução de Sinais/genética , Baço/citologia , Baço/imunologia , Baço/metabolismo , Transativadores/deficiência , Transativadores/genética , Transativadores/metabolismoRESUMO
The interleukin 7 receptor alpha-chain (IL-7Ralpha) is essential for T cell development in both humans and mice and for B cell development in mice. Whereas the transcription factor PU.1 regulates IL-7Ralpha expression in mouse pro-B cells via a GGAA motif, we demonstrate here that GA binding protein (GABP) bound to this site and was essential in the regulation of IL-7Ralpha expression in T cells, where PU.1 is not expressed. Moreover, IL-7Ralpha expression was diminished substantially in thymocytes but was normal on B220(+) fetal liver cells from mouse embryos with diminished expression of GABPalpha. Thus, GABP is essential for the regulation of IL-7Ralpha expression in T cells, and the differential regulation of IL-7Ralpha in distinct lymphoid lineages is achieved at least in part by differential recruitment of factors to the same GGAA motif.