RESUMEN
The transcription factors T-bet and Bcl-6 are required for the establishment of a T helper type 1 cell (T(H)1 cell) and follicular helper T cell (T(FH) cell) gene-expression profile, respectively. Here we found that high concentrations of interleukin 2 (IL-2) inhibited Bcl-6 expression in polarized T(H)1 cells. Mechanistically, the low concentrations of Bcl-6 normally found in effector T(H)1 cells did not repress its target genes because a T-bet-Bcl-6 complex masked the Bcl-6 DNA-binding domain. T(H)1 cells increased their Bcl-6/T-bet ratio in response to limiting IL-2 conditions, which allowed excess Bcl-6 to repress its direct target Prdm1 (which encodes the transcriptional repressor Blimp-1). The Bcl-6-dependent repression of Blimp-1 effectively induced a partial T(FH) profile because Blimp-1 directly repressed a subset of T(FH) signature genes, including Cxcr5. Thus, IL-2-signaling regulates the Bcl-6-Blimp-1 axis in T(H)1 cells to maintain flexibility with a T(FH) cell-like gene profile.
Asunto(s)
Diferenciación Celular/genética , Regulación de la Expresión Génica/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/genética , Subgrupos de Linfocitos T/citología , Células TH1/citología , Animales , Diferenciación Celular/inmunología , Células Cultivadas , Perfilación de la Expresión Génica , Immunoblotting , Inmunoprecipitación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-bcl-6/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/genética , Transducción de Señal/inmunología , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Subgrupos de Linfocitos T/inmunología , Células TH1/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo , TransfecciónRESUMEN
The stable and heritable H3K27-methyl mark suppresses transcription of lineage-specific genes in progenitor cells. During developmental transitions, histone demethylases are required to dramatically alter epigenetic and gene expression states to create new cell-specific profiles. It is unclear why demethylase proteins that antagonize polycomb-mediated repression continue to be expressed in terminally differentiated cells where further changes in H3K27 methylation could be deleterious. In this study, we show that the H3K27 demethylases, Jmjd3 and UTX, mediate a functional interaction between the lineage-defining T-box transcription factor family and a Brg1-containing SWI/SNF remodeling complex. Importantly, Jmjd3 is required for the coprecipitation of Brg1 with the T-box factor, T-bet, and this interaction is necessary for Ifng remodeling in differentiated Th1 cells. Thus, Jmjd3 has a required role in general chromatin remodeling that is independent from its H3K27 demethylase potential. This function for H3K27 demethylase proteins may explain their presence in differentiated cells where the epigenetic profile is already established.