Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction.
Type 1 helper T (T(H)1) 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(H)1 gene expression. Optimal induction of interferon-gamma (IFN-gamma) expression required genetic interaction between T-bet and its target, the homeoprotein Hlx. In fully mature T(H)1 cells, reiteration of IFN-gamma 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-12R beta 2 (interleukin 12 receptor beta 2), required ongoing T-bet activity in mature T(H)1 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.
Mullen
Alan C
AC
Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
Hutchins
Anne S
AS
High
Frances A
FA
Lee
Hubert W
HW
Sykes
Kara J
KJ
Chodosh
Lewis A
LA
Reiner
Steven L
SL
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000502:physiology; D019175:DNA Methylation; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics; D053707:Receptors, Interleukin-12; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000098815:T-bet Transcription Factor
D002843:Chromatin; C084058:HLX protein, human; C489999:Hlx protein, mouse; D018398:Homeodomain Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011993:Recombinant Fusion Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma