Conventional dendritic cells (cDCs) include functionally and phenotypically diverse populations, such as cDC1s and cDC2s. The latter population has been variously subdivided into Notch-dependent cDC2s, KLF4-dependent cDC2s, T-bet⁺ cDC2As and T-bet⁻ cDC2Bs, but it is unclear how all these subtypes are interrelated and to what degree they represent cell states or cell subsets. All cDCs are derived from bone marrow progenitors called pre-cDCs, which circulate through the blood to colonize peripheral tissues. Here, we identified distinct mouse pre-cDC2 subsets biased to give rise to cDC2As or cDC2Bs. We showed that a Siglec-H⁺ pre-cDC2A population in the bone marrow preferentially gave rise to Siglec-H⁻ CD8α⁺ pre-cDC2As in tissues, which differentiated into T-bet⁺ cDC2As. In contrast, a Siglec-H⁻ fraction of pre-cDCs in the bone marrow and periphery mostly generated T-bet⁻ cDC2Bs, a lineage marked by the expression of LysM. Our results showed that cDC2A versus cDC2B fate specification starts in the bone marrow and suggest that cDC2 subsets are ontogenetically determined lineages, rather than cell states imposed by the peripheral tissue environment.

传统的树突状细胞 (cDC) 包括功能和表型多样化的群体，例如 cDC1 和 cDC2。后者群体已被不同地细分为Notch依赖性cDC2、KLF4依赖性cDC2、T-bet ⁺ cDC2As和T-bet ^- cDC2B，但尚不清楚所有这些亚型如何相互关联以及它们在多大程度上代表细胞状态或细胞子集。所有 cDC 均源自称为前 cDC 的骨髓祖细胞，它们通过血液循环定植于外周组织。在这里，我们鉴定了不同的小鼠前 cDC2 子集，这些子集偏向于产生 cDC2A 或 cDC2B。我们发现，骨髓中的 Siglec-H ⁺ pre-cDC2A 群体优先在组织中产生 Siglec-H ^- CD8α ⁺ pre-cDC2As，并分化为 T-bet ⁺ cDC2As。相比之下，骨髓和外周中的 Siglec-H ^-前 cDC 部分主要生成 T-bet ^- cDC2B，这是一个以 LysM 表达为标志的谱系。我们的结果表明，cDC2A 与 cDC2B 的命运规范始于骨髓，并表明 cDC2 亚群是个体发育决定的谱系，而不是由周围组织环境强加的细胞状态。