近日，英国伯明翰大学David R. Withers、曼切斯特大学Matthew R. Hepworth等研究人员合作发现，相反的转录因子网络调控组织驻留ILC3亚群的功能和特性。该研究于2021年9月23日在线发表于国际一流学术期刊《自然—免疫学》。

研究人员使用诱导性组合缺失先天性淋巴细胞（ILC）发育所需的关键转录因子（RORγt、RORα和T-bet），来确定了它们在维持ILC3特性和功能方面的必要性。RORγt和RORα都是保持最佳效应功能所必需的；然而，RORα足以支持淋巴组织诱导者（LTi）样ILC3亚群的强大白细胞介素-22生产，但不支持天然细胞毒性受体（NCR）⁺ ILC3。淋巴组织诱导者样ILC3持续存在，即使在失去这两种转录因子后，也只是选择性地丧失表型和效应功能。

相反，RORγt的持续表达对抑制NCR⁺ ILC3内与1型免疫相关的转录网络至关重要，这些ILC3共同表达T-bet。完全分化为ILC1样的群体需要额外失去RORα。这些数据表明，转录因子网络是如何在发育后整合到成熟的ILC中，从而维持效应功能、印记表型并限制替代分化程序。

据悉，ILC是粘膜免疫的守护者，然而支持其功能的转录网络仍然知之甚少。

附：英文原文

Title: Reciprocal transcription factor networks govern tissue-resident ILC3 subset function and identity

Author: Fiancette, Rmi, Finlay, Conor M., Willis, Claire, Bevington, Sarah L., Soley, Jake, Ng, Sky T. H., Baker, Syed Murtuza, Andrews, Simon, Hepworth, Matthew R., Withers, David R.

Issue&Volume: 2021-09-23

Abstract: Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)+ ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR+ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.

DOI: 10.1038/s41590-021-01024-x

Source: https://www.nature.com/articles/s41590-021-01024-x