Abstract
Gaining a mechanistic understanding of the expansion and maturation program of natural killer (NK) cells will provide opportunities for harnessing their inflammation-inducing and oncolytic capacity for therapeutic purposes. Here, we demonstrated that ID2, a transcriptional regulatory protein constitutively expressed in NK cells, supports NK cell effector maturation by controlling the amplitude and temporal dynamics of the transcription factor TCF1. TCF1 promotes immature NK cell expansion and restrains differentiation. The increased TCF1 expression in ID2-deficient NK cells arrests their maturation and alters cell surface receptor expression. Moreover, TCF1 limits NK cell functions, such as cytokine-induced IFN-γ production and the ability to clear metastatic melanoma in ID2-deficient NK cells. Our data demonstrate that ID2 sets a threshold for TCF1 during NK cell development, thus controlling the balance of immature and terminally differentiated cells that support future NK cell responses.
| Original language | English (US) |
|---|---|
| Article number | e20202032 |
| Journal | Journal of Experimental Medicine |
| Volume | 218 |
| Issue number | 6 |
| DOIs | |
| State | Published - Apr 15 2021 |
Funding
We thank the members of the Kee Lab and M. Verykokakis for helpful conversations and comments on the manuscript, G. van der Voort and S. Cuthbert for technical assistance, T. Gajewski (University of Chicago, Chicago, IL) for the B16-F10 melanoma cells, E. Vivier for the Ncr1Cre mice, and F. Gounari for the Tcf7F/F mice and for helpful discussions. We thank the Cytometry and Antibody Technology and the Functional Genomics Facility cores at The University of Chicago and The University of Chicago Comprehensive Cancer Center for support. This work was supported by National Institutes of Allergy and Infectious Diseases grants R01 AI106352 (B.L. Kee) and National Cancer Institute grant P30 CA014599 (The University of Chicago Comprehensive Cancer Center).
ASJC Scopus subject areas
- General Medicine