T-bet employs diverse regulatory mechanisms to repress transcription.

Lineage-defining transcription factors are responsible for activating the signature genes required for a given cell fate. They are also needed to repress the genetic programs associated with alternative lineage decisions. The T-box transcription factor T-bet is required for CD4(+) T helper 1 (Th1) cell differentiation. Numerous studies have explored the mechanisms by which T-bet activates the Th1 gene profile, but until recently not much was known about the mechanisms that T-bet utilizes to negatively regulate alternative T helper cell differentiation pathways such as the Th2 and Th17 fates. Here, we discuss new advances in the field that highlight the diverse mechanisms that T-bet employs to antagonize the gene programs for alternative T helper cell fates.