transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 42; pp. 17876 - 17881
• Main Authors: Jenner, Richard G, Townsend, Michael J, Jackson, Ian, Sun, Kaiming, Bouwman, Russell D, Young, Richard A, Glimcher, Laurie H, Lord, Graham M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.10.2009; National Acad Sciences
• Subjects: Antibodies; Antigens; Biological Sciences; Cell Differentiation - genetics; Cell Differentiation - immunology; Cells; Cellular differentiation; Chromatin Immunoprecipitation; GATA3 Transcription Factor - immunology; GATA3 Transcription Factor - metabolism; Gene expression; Genes; Genes, MHC Class II; Genomics; Humans; In Vitro Techniques; Mice; Natural killer cells; Natural killer T cells; Oligonucleotide Array Sequence Analysis; Pathogens; T cell receptors; T lymphocytes; T-Box Domain Proteins - immunology; T-Box Domain Proteins - metabolism; Th1 Cells - cytology; Th1 Cells - immunology; Th1 Cells - metabolism; Th2 Cells - cytology; Th2 Cells - immunology; Th2 Cells - metabolism; Transcription factors; Transcriptional Activation - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0909357106

Upon detection of antigen, CD4⁺ T helper (Th) cells can differentiate into a number of effector types that tailor the immune response to different pathogens. Alternative Th1 and Th2 cell fates are specified by the transcription factors T-bet and GATA-3, respectively. Only a handful of target genes are known for these two factors and because of this, the mechanism through which T-bet and GATA-3 induce differentiation toward alternative cell fates is not fully understood. Here, we provide a genomic map of T-bet and GATA-3 binding in primary human T cells and identify their target genes, most of which are previously unknown. In Th1 cells, T-bet associates with genes of diverse function, including those with roles in transcriptional regulation, chemotaxis and adhesion. GATA-3 occupies genes in both Th1 and Th2 cells and, unexpectedly, shares a large proportion of targets with T-bet. Re-complementation of T-bet alters the expression of these genes in a manner that mirrors their differential expression between Th1 and Th2 lineages. These data show that the choice between Th1 and Th2 lineage commitment is the result of the opposing action of T-bet and GATA-3 at a shared set of target genes and may provide a general paradigm for the interaction of lineage-specifying transcription factors.