A key unsolved question regarding the developmental origin of conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) resident in the steady-state thymus is whether early thymic progenitors (ETPs) could escape T cell fate constraints imposed normally by a Notch-inductive microenvironment and undergo DC development. By modeling DC generation in bulk and clonal cultures, we show here that Jagged1 (JAG1)-mediated Notch signaling allows human ETPs to undertake a myeloid transcriptional program, resulting in GATA2-dependent generation of CD34⁺ CD123⁺ progenitors with restricted pDC, cDC, and monocyte potential, whereas Delta-like1 signaling down-regulates GATA2 and impairs myeloid development. Progressive commitment to the DC lineage also occurs intrathymically, as myeloid-primed CD123⁺ monocyte/DC and common DC progenitors, equivalent to those previously identified in the bone marrow, are resident in the normal human thymus. The identification of a discrete JAG1⁺ thymic medullary niche enriched for DC-lineage cells expressing Notch receptors further validates the human thymus as a DC-poietic organ, which provides selective microenvironments permissive for DC development.

有关驻留在稳态胸腺中的常规和浆细胞样树突状细胞（分别为cDC和pDC）的发育起源的一个关键悬而未决的问题是，早期胸腺祖细胞（ETP）是否能逃脱通常由Notch诱导微环境施加的T细胞命运限制并进行DC开发。通过在批量和克隆培养中模拟DC生成，我们在这里显示Jagged1（JAG1）介导的Notch信号允许人类ETP进行髓样转录程序，从而导致CD34 ⁺ CD123 ^+的GATA2依赖性生成具有限制的pDC，cDC和单核细胞潜能的祖细胞，而Delta-like1信号下调GATA2并损害髓样细胞的发育。对DC谱系的逐步承诺也发生在胸腺内，因为正常人胸腺中常存在髓样的CD123 ⁺单核细胞/ DC和常见的DC祖细胞（与先前在骨髓中鉴定出的相同）。对表达Notch受体的DC谱系细胞富集的离散JAG1 ⁺胸腺髓质生态位的鉴定进一步验证了人胸腺作为DC的器官，它为DC的发展提供了选择性的微环境。