The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL⁺SIGLEC6⁺ pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using high-dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c⁺DC) heterogeneity originates from two distinct pathways of development. The lymphoid-primed IRF8^hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8^lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL⁺SIGLEC6⁺ pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency.

哺乳动物树突状细胞（DCs）的形成受多种造血转录因子（包括IRF8）控制。IRF8的丢失对DC子集（包括浆细胞样DC（pDC）和经典DC谱系cDC1和cDC2）产生不同的影响。在人类中，已经描述了与cDC2相关的子集，包括AXL ⁺ SIGLEC6 ⁺ pre-DC，DC2和DC3。这种异质性的起源是未知的。使用高维分析，体外分化和人类IRF8缺乏等位基因系列，我们证明了cDC2（CD1c ⁺ DC）异质性源于两个不同的发展途径。淋巴引发的IRF8^高CD123和BTLA标记的CD3通路带有pDC，cDC1和DC2轨迹，而表达SIRPA的常见髓样IRF8 ^lo通路则形成DC3和单核细胞。我们通过粒细胞-巨噬细胞祖细胞（GMP）室追踪了不同的轨迹，表明AXL ⁺ SIGLEC6 ⁺ pre-DC仅映射到DC2途径。为了满足对IRF8的较低要求，DC3扩展为替代人类部分IRF8缺乏症中的DC2。