T-lymphocytes are vital components of the immune system in humans and other mammals. They are generated by multiple waves of blood cell precursors that migrate from the bone marrow to a special organ, the thymus, where the stem cell-like precursor cells encounter signals that cause them to differentiate into T cells. This process is important for health by providing resistance to infection and cancer, and it is also very illuminating as a model system to show how environmental signaling, endogenously expressed transcription factors, and epigenetic chromatin changes can work together in an orderly, stepwise process to convert cells efficiently from stem-like cells to effective, useful differentiated cells. We can “zoom in” to observe and dissect this process through powerful in vitro culture systems that mimic the thymus in an open format, which allows the developing cells to be observed and manipulated.

The Rothenberg lab has focused on answering three kinds of questions. First, how do the transcription factors in these cells act in a cascade, so that each transcription factor works to activate or shut off other transcription factors in an orderly way, which then themselves change the expression of another set of genes? Second, how does the epigenetic state of the chromatin affect what these transcription factors can do at a given stage, and how do the factors themselves alter the epigenetic state to allow differentiation to proceed? Third, how do these mechanisms explain the high efficiency but slow speed of this developmental process? The talk will show how recent results shed light on these questions.