T cell lineage commitment: identity and renunciation1

Precursors undertaking T-cell development shed their access to other pathways in a sequential process that begins before entry into the thymus and continues through many cell cycles afterwards. This process involves three levels of regulatory change, in which the cells’ intrinsic transcriptional regulatory factors, expression of signaling receptors like Notch1, and expression of distinct homing receptors separately contribute to confirmation of T-cell identity. Each alternative potential has a different underlying molecular basis which is neutralized, then permanently silenced through different mechanisms in early T-cell precursors. This regulatory mosaic has notable implications for the hierarchy of relationships linking T lymphocytes to other hematopoietic fates. Commitment versus potential Multipotent hematopoietic cells gain access to the T-cell developmental pathway, and then confirm that choice of fate by “burning their bridges” to other pathways. The process involves a continuing dialogue between the differentiating cell and the signals coming from its environment. Best understood of these signals are effects of Notch1 engagement with Delta ligands provided in the environment of the thymus, which are needed for T-cell specification throughout the lineage choice process, and only become dispensable after Tcell fate is confirmed (1-3). In vivo, expression of Notch ligand with supportive cytokines such as IL-7 and Kit ligand gives the thymus its T-cell inductive activity (3). However, the cells that begin the T cell program initially have access to other options. These can be revealed if the cells are removed from the thymic environment and challenged with different environmental signals. Only after they lose the ability to make these alternative responses are the cells committed. Commitment is the cell-intrinsic regulatory transformation through which a cell's alternative potentials are eliminated. “Potential” is not the same as the default fate that a cell adopts in an undisturbed condition. “Fate” is the intersection between the cell's potential and the permissive or nonpermissive circumstances in which a cell finds itself. For a typical uncommitted cell, the fates its progeny actually adopt in vivo may be only a slice of the uncommitted cell's full potential, because environmental conditions are limiting. As the cell progresses toward commitment, its potential shrinks. At the point where potential rather than environment becomes limiting for fate, the cell is committed. Interestingly, one of the few cases where a “fate” assay approaches a “potential” assay is in the case of hematopoietic stem cells, where extremely long assay times are conventionally used, extremely large numbers of progeny are generated before the endpoint, and the intermediates include highly motile cells that can sample an unusually large number of in vivo environments before 1Support was from USPHS grants CA90233, HL089123, DK073658, CA98925, CA148278, and AI083514, and the Albert Billings Ruddock Professorship at Caltech. Tel 1-626-395-4992 Fax 1-626-449-0756 [email protected]. NIH Public Access