In this

issue of the European Journal of Immunology, a study reports the identification of an intrathymic DC precursor that is likely to be unrelated to the earliest physiological T-cell progenitors. Thus this intrathymic DC precursor may constitute a “missing link” between extrathymic DC precursor-types, which are able to generate DCs in secondary lymphoid organs and intrathymic DCs, and supports the notion that intrathymic DCs and thymocytes arise from different precursors. DCs epitomize antigen-presenting cells, thus initiating adaptive immune responses in secondary lymphoid organs (SLOs). In addition, DCs contribute to the deletion of autoreactive thymocytes during negative selection in the thymus. Within the lymphoid organs, non-migratory DCs can be subdivided learn more into plasmacytoid Talazoparib (p)DCs and two populations of classical (c)DCs, which play different roles in antigen presentation. Phenotypically, these two cDC subsets can be distinguished as CD8α+ and CD8α− DCs 1. The expression of the bona fide lymphoid marker CD8α on one of these subsets of cDCs suggested that this subset is of lymphoid

origin, whereas the CD8α− cDCs are of myeloid origin. However, it has become increasingly clear that both types of cDCs residing in SLOs are mostly of myeloid origin, although lymphoid progenitors may, to a minor extent, feed into the cDC lineage 2, 3. The recent identification of a series of progressively lineage-restricted DC progenitor populations has established a firm link between DCs and myeloid progenitors 4. In contrast, the origin of CD8α+ thymic (t)DCs remains elusive and controversial. On the one hand, a considerable body of evidence points to a lymphoid past for these cells and on the other hand, intrathymic committed DC precursors had remained undetected. Thus, whereas CD8α+ tDCs harbor Phosphoprotein phosphatase DHJH rearrangements, such rearrangements are virtually absent in splenic CD8α+ DCs 5. In addition, both human and mouse tDCs have been reported to express the pre-TCRα chain 3, 6. Furthermore, the earliest intrathymic T-cell precursors and even later

developmental stages along the T lineage have been shown to be able to generate DCs, and CD8α+ tDCs develop intrathymically with kinetics paralleling those of T cells 7–9. In this issue of the European Journal of Immunology, Luche et al. report the identification of an intrathymic DC precursor, which is distinct from the earliest canonical T-cell precursors and bears phenotypic similarities to extrathymic pre-DCs 10. Thus, Luche et al. provide a “missing link” between the recently established differentiation pathway of DCs residing in SLOs and tDCs, suggesting that the developmental origin of CD8α+ tDCs might, in fact, not be dissimilar to that of other CD8α+ DCs. Phenotypically, this novel DC precursor is located within the so-called double negative (DN1c) population of thymocytes, based on the nomenclature introduced by Petrie and colleagues 11.