Abstract

Naïve T helper cells differentiate into two subsets, T helper 1 and 2, which either transcribe the Ifng gene and silence the Il4 gene or transcribe the Il4 gene and silence the Ifng gene, respectively. This process is an essential feature of the adaptive immune response to a pathogen and the development of long-lasting immunity. The 'histone code' hypothesis proposes that formation of stable epigenetic histone marks at a gene locus that activate or repress transcription is essential for cell fate determinations, such as T helper 1/T helper 2 cell fate decisions. Activation and silencing of the Ifng gene are achieved through the creation of stable epigenetic histone marks spanning a region of genomic DNA over 20 times greater than the gene itself. Key transcription factors that drive the T helper 1 lineage decision, signal transducer and activator 4 (STAT4) and T-box expressed in T cells (T-bet), play direct roles in the formation of activating histone marks at the Ifng locus. Conversely, STAT6 and GATA binding protein 3, transcription factors essential for the T helper 2 cell lineage decision, establish repressive histone marks at the Ifng locus. Functional studies demonstrate that multiple genomic elements up to 50 kilobases from Ifng play critical roles in its proper transcriptional regulation. Studies of three-dimensional chromatin conformation indicate that these distal regulatory elements may loop towards Ifng to regulate its transcription. We speculate that these complex mechanisms have evolved to tightly control levels of interferon-gamma production, given that too little or too much production would be very deleterious to the host.