Deciphering how transcription factors establish T cell fate

Our protection against microorganisms such as viruses, bacteria, and fungi is achieved by the orchestrated interactions among a multitude of distinct and specific cells of the innate and adaptive immune responses. Among many players in this system, the white blood cells called T lymphocytes possess the most powerful ability to recognize and target the pathogenic microorganisms. Despite decades of studies defining proteins functionally required for T cell development, the detailed molecular mechanisms through which the chromatin of T cells becomes unpacked are not clearly understood. The first independent study from our laboratory filled this gap. We demonstrated for the first time that a transcription factor called TCF-1, which has been known to be required for T cell development for two decades, has an exceptional property to unwrap DNA from nucleosomes and create open chromatin, establishing the epigenetic identity of T cells (Johnson et al., 2018).

Strikingly, we found that the ectopic expression of TCF-1 in fibroblasts can unwrap DNA from nucleosomes even at stretches with the most refractory chromatin states, leading to gene expression. These findings have been recognized as a paradigm shift in how T cell commitment is regulated. Importantly, this discovery laid the groundwork for ongoing studies in our laboratory. We aim to elucidate the precise epigenetic mechanisms through which TCF-1 interacts with chromatin remodeling enzymes to unwrap DNA from nucleosomes, thus leading to a highly orchestrated cascade of gene expression events that drive T cell development and function. A detailed molecular understanding of the interactions between transcription factors and chromatin remodelers in packaging of DNA into chromatin in T cells is a significant contribution since it forms the foundation for the development of highly selective and efficient strategies including epigenetic therapies that could alter T cell fate and function at will.