The intrathymic crossroads of T and NK cell differentiation

T lymphocytes depend on the thymic microenvironment for initiation of the T-cell developmental program. As the progenitors in the thymus have lost the capacity to self-renew, this process depends on the constant influx of hematopoietic progenitors that originate in the bone marrow. Nevertheless, thymic emigrants are heterogeneous and retain developmental plasticity for both the myeloid and lymphoid lineages. It is the role of the thymic microenvironment to steer these uncommitted progenitors toward a T-cell fate. Still, the thymus also generates a unique population of thymic NK cells, thus raising the question of how the T versus NK lymphoid cell fate is determined intrathymically. Many factors have been implicated in the developmental pathways in the thymus, and the processes are characterized by both subtle and not so subtle modifications in gene expression. In this review, we consider the crucial factors governing lineage determination of T cells versus NK cells from bi-potent thymic NK/T precursors. Recent reports have shed new light on the complex interactions of cytokines and transcription factors at different cell fate decision branch points in thymopoiesis. We discuss the implications of these findings and propose a model that may be applicable at this critical thymic NK/T juncture.