Helper T cell differentiation as a model for chromatin-based gene silencing

During an immune response, a naive CD4+ helper T cell undergoes a program of proliferation and differentiation, which can lead to the development of Th1- and Th2-type effector cells. Th1- and Th2-type cells, which arise from a common multipotent naive T cell, differ in both their transcriptional programs and in the chromatin structure of their lineage markers, interferon gamma (IFN-γ) and interleukin 4 (IL-4), respectively. T-bet and GATA-3 play essential roles in establishing transcriptional competence of the Ifng and Il4 gene, respectively. The progenitor cell expresses both lineage commitment factors, T-bet and GATA-3, in a cell cycle-independent manner; yet does not express the signature genes of differentiated lineages. Given that T-bet and GATA-3 are expressed prior to entry into the cell cycle, this suggests that transcription factor composition is not fully deterministic of a cell\u27s fate. This model suggests that a cell\u27s repertoire of activators may be restrained from directing cell fate decisions by repressive chromatin structures of their target genes. To explore the role of gene silencing in helper T cell differentiation, I examined terminal differentiation in cells lacking methyl CpG-binding domain protein-2 (MBD2), a molecule that has been proposed to link DNA methylation to chromatin-based silencing. I found that helper T cells from Mbd2−/− mice exhibit disordered differentiation. MBD2 appears to have a role in limiting IFN-γ and IL-4 expression during development to the appropriate set of restricted progeny. The trans-activators T-bet and GATA-3 appear to act in competition with MBD2, wherein each factor independently, and quantitatively, regulates the binary choice of whether heritable IFN-γ and IL-4 expression is established, respectively. Although MBD2 and GATA-3 seem to independently regulate IL-4 expression, they also appear to be interconnected. This data highlights novel roles for transcriptional activators and chromatin-based repressors in the developmentally regulated induction of IFN-γ and IL-4. Furthermore, these results suggest that activating and silencing signals integrate to provide spatially and temporally restricted patterns of gene activity.