The Heart of the Machine: Construction of T Cell Identity, Made Accessible

Abstract

Twenty years ago, a paper appeared that catalyzed the emergence of a field. Schmitt and Zúñiga-Pflücker described a new monolayer-based tissue culture system in which T cell development from hematopoietic precursors could be supported in vitro outside of the thymus. At a stroke, this work resolved debates about key functions of the thymic epithelium, revealed steps in early T cell differentiation with unprecedented precision, allowed T cell lineage commitment to be studied quantitatively, and created an experimental framework for connecting the T cell lineage to the whole range of other hematolymphoid developmental pathways. As subsequent work showed, the system developed by Schmitt and Zúñiga-Pflücker allowed efficient, routine T lineage development from single progenitor cells, enabling rigorous study of cell fate determination at a clonal level. It also opened up the black box of the thymus, enabling genetic perturbation and titration studies that created a foundation for a molecular understanding of the process through which cells enter into the T cell pathway. Even though this system did not go all the way to generate functional mature T cells, it paved the way for work in numerous other laboratories, ultimately helping to make T cell development one of the best understood developmental systems in mammalian biology.