Innate lymphoid cells (ILCs) participate in tissue homeostasis, inflammation, and early immunity against infection. It is unclear how ILCs acquire effector function and whether these mechanisms differ between organs. Through multiplexed single-cell mRNA sequencing, we identified cKit⁺CD127^hiTCF-1^hi early differentiation stages of T-bet⁺ ILC1s. These cells were present across different organs and had the potential to mature toward CD127^intTCF-1^int and CD127⁻TCF-1⁻ ILC1s. Paralleling a gradual loss of TCF-1, differentiating ILC1s forfeited their expansion potential while increasing expression of effector molecules, reminiscent of T cell differentiation in secondary lymphoid organs. The transcription factor Hobit was induced in TCF-1^hi ILC1s and was required for their effector differentiation. These findings reveal sequential mechanisms of ILC1 lineage commitment and effector differentiation that are conserved across tissues. Our analyses suggest that ILC1s emerge as TCF-1^hi cells in the periphery and acquire a spectrum of organ-specific effector phenotypes through a uniform Hobit-dependent differentiation pathway driven by local cues.

先天淋巴细胞 (ILC) 参与组织稳态、炎症和针对感染的早期免疫。目前尚不清楚 ILC 如何获得效应功能以及这些机制在器官之间是否存在差异。通过多重单细胞 mRNA 测序，我们鉴定了 cKit ⁺ CD127 ^hi TCF-1 ^hi T-bet ⁺ ILC1s 的早期分化阶段。这些细胞存在于不同的器官中，并有可能向 CD127 ^int TCF-1 ^int和 CD127 ^- TCF-1 ^-成熟ILC1s。在 TCF-1 逐渐丧失的同时，分化的 ILC1 丧失了它们的扩张潜力，同时增加了效应分子的表达，这让人想起次级淋巴器官中的 T 细胞分化。转录因子 Hobit 在 TCF-1 ^hi ILC1s 中被诱导，并且是它们的效应分化所必需的。这些发现揭示了跨组织保守的 ILC1 谱系定型和效应分化的顺序机制。我们的分析表明，ILC1 在外围以 TCF-1 ^hi细胞的形式出现，并通过由局部线索驱动的统一的 Hobit 依赖性分化途径获得一系列器官特异性效应表型。