When do thymic precursors commit?

A recent report in The Journal of Experimental Medicine sheds light on two longstanding and much debated questions in thymopoiesis research. What are the first haematopoietic precursors that seed the thymus? And when do thymic precursors commit to the T-cell lineage? By studying the clonal differentiation potential of the most immature precursors in the thymus, Claudia Benz and Conrad Bleul identify, on a single-cell level, the first multipotent precursor in the thymus and indicate that, for some progenitor cells, commitment to the T-cell fate occurs after arrival in the thymus.

Populations of precursors in the thymus can produce T cells, B cells and dendritic cells (DCs), but it is still unclear whether these cell types are derived from a single multipotent progenitor or from distinct pre-committed precursor cells. To address this, the authors generated mice in which T-lineage cells were tagged by expression of enhanced green fluorescent protein (EGFP) from the CC-chemokine receptor 9 (CCR9) locus, which is expressed at sites of T-cell development. In these mice, they identified Lin⁻CD25⁻CD117⁺EGFP⁺ thymic precursor populations in the bone marrow, blood and thymus, and these contained T-lineage precursors that could give rise to all of the stages of T-cell development when cultured under appropriate conditions. This indicates that the Lin⁻CD25⁻CD117⁺EGFP⁺ precursors are likely to be thymus-repopulating cells that travel from the bone marrow to the thymus through the blood. By taking advantage of the different levels of EGFP expression among early thymic progenitors, they showed that the most immature precursors had the highest levels of EGFP expression in the thymus and had a differentiation potential that closely resembled that of the precursors in the blood. In addition to T cells, these EGFP^hi thymic precursors could give rise to B cells, natural killer cells, DCs and myeloid cells. By contrast, the EGFP^low population did not give rise to B cells, indicating that the EGFP^hi population marks the branching point of the T- and B-cell lineages. Moreover, by single-cell cloning, they confirmed that a single EGFP^hi cell could give rise to all of the haematopoietic lineages that are known to develop in the thymus, indicating that these thymic precursors enter the thymus as multipotent progenitors and commit to the T-cell lineage in the thymus and not before.