T cell factor-1 is a Critical Factor in Determining Natural Killer and Group 1 Innate Lymphoid Cell Fate Decisions
Lisa A Mielke1, 2, Qiutong Huang1, 2, Matthew A Firth1, 2, Francisca F Almeida1, 2, Hesham Abdulla1, 2, Jai Rautela1, 2, Swee Heng Milon Pang1, 2, Waruni Abeysekera1, 3, Hai-Hui Xue5, Nicholas D Huntington1, 2, Gordon K Smyth1, 3, Alexandra L Garnham1, 3, Matthew P McCormack1, 4, Eric Vivier6, 7, Cyril Seillet1, 2, Gabrielle Belz T Belz1, 2
1Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia, 2Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Australia, 3Department of Mathematics and Statistics, University of Melbourne, Parkville, Melbourne, Australia, 4Australian Centre for Blood Diseases, Monash University, Melbourne, Australia, 5Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, United States, 6Centre d’Immunologie de Marseille-Luminy, Aix-Marseille University, INSERM, CNRS, Marseille, France, 7Immunologie, Hôpital de la Timone, Assistance Publique – Hôpitaux de Marseille, Marseille, France
Protection against infections and malignancies depends on the coordinate development and cytokine production of immune cells. T cell factor 1 (TCF-1) is a transcriptional regulator of both adaptive T cells and innate lymphoid cells (ILC), but how this factor drives their development remains unclear. We found that TCF-1 acted in the thymus as a critical checkpoint to limit the expression of signature NK cell genes. De-repression of this thymic checkpoint resulted in the development of thymic-derived NK-like cells that could reconstitute the entire peripheral compartment and were capable of preventing tumour establishment. We also show that TCF-1 is required downstream of the common ILC progenitor to establish the ILC1 lineage by directing ILC1-specific progenitors cells, but it was not required for maintenance of mature ILC2 or ILC3 cells. Collectively, our data reveal the complexity of the role of TCF-1 as a molecular switch regulating the fate decisions in controlling adaptive T cells vs NK cell fate and ILC1 development.