HSPH professor Laurie Glimcher and her colleagues, including research associate Eun-Sook Hwang, have identified a genetic switch that determines which developmental path young T cells will follow. The work, published in today’s issue of Science, shows how one protein, T-bet, functions in two different ways in Th1 cell development to simultaneously turn on the Th1 gene program and switch off Th2 genes.

	Above, at right, the transcription factor GATA3 must interact with specific promoters to activate Th2 genes. At left, T-bet interferes with the process, effectively silencing the Th2 genes.

The T-bet protein was recognized as central to the seesaw gene regulation in T cell development right from its first discovery in Glimcher’s lab four years ago. But while researchers knew early on that the protein could act as a transcription factor that attached to the DNA of Th1 genes and turned them on, no one understood how it turned off the Th2 program.

The answer lies in the action of a molecule called protein tyrosine kinase enzyme (ITK), which adds a single phosphate molecule to T-bet after the cells have been stimulated with an antigen. This phosphorylation silences Th2 gene activity by tying up a major activator of its genes, a transcription factor called GATA3.

--PM