Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction

Abstract

Type 1 helper T (T_H1) cells are essential for cellular immunity, but their ontogeny, maturation and durability remain poorly understood. By constructing a dominant-negative form of T-bet, we were able to determine the role played by this lineage-inducing trans-activator in the establishment and maintenance of heritable T_H1 gene expression. Optimal induction of interferon-γ (IFN-γ) expression required genetic interaction between T-bet and its target, the homeoprotein Hlx. In fully mature T_H1 cells, reiteration of IFN-γ expression and stable chromatin remodeling became relatively independent of T-bet activity and coincided with demethylation of DNA. In contrast, some lineage attributes, such as expression of IL-12Rβ2 (interleukin 12 receptor β2), required ongoing T-bet activity in mature T_H1 cells and their progeny. These findings suggest that heritable states of gene expression might be maintained by continued expression of the inducing factor or by a mechanism that confers a stable imprint of the induced state.