Key Points
Homeostatic turnover generates heterogeneity in cell age among naive group 1 ILCs.
Turnover of tissue-resident ILC1s is slower than that of circulating NK cells.
Older NK cells mount more robust adaptive responses during CMV infection.
Visual Abstract
Abstract
Heterogeneity among naive adaptive lymphocytes determines their individual functions and fate decisions during an immune response. NK cells are innate lymphocytes capable of generating “adaptive” responses during infectious challenges. However, the factors that govern various NK cell functions are not fully understood. In this study, we use a reporter mouse model to permanently “time stamp” NK cells and type 1 innate lymphoid cells (ILC1s) to characterize the dynamics of their homeostatic turnover. We found that the homeostatic turnover of tissue-resident ILC1s is much slower than that of circulating NK cells. NK cell homeostatic turnover is further accelerated without the transcription factor Eomes. Finally, heterogeneity in NK cell age diversifies NK cell function, with “older” NK cells exhibiting more potent IFN-γ production to activating stimuli and more robust adaptive responses during CMV infection. These results provide insight into how the functional response of an NK cell varies over its lifespan.
Footnotes
This work was supported by National Institutes of Health Grants AI068129 (to L.L.L.), AI100874, AI130043, and P30CA008748 (all to J.C.S.). N.M.A. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences (T32GM007739 to the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program) and by an F30 Predoctoral Fellowship from the National Institute of Allergy and Infectious Diseases (F30 AI136239). C.D.-S. was supported by a Fulbright Fellowship from the Commission for Cultural, Educational and Scientific Exchange between the United States and Spain. L.L.L. is supported by the Parker Institute for Cancer Immunotherapy. J.C.S. is supported by the Ludwig Center for Cancer Immunotherapy, the American Cancer Society, and the Burroughs Wellcome Fund.
Abbreviations used in this article:
- EomesΔ/Δ
- iNkp46tdTomatoEomesfl/fl
- Eomes
- Eomesodermin
- ILC1
- type 1 innate lymphoid cell
- iNkp46tdTomato
- Nkp46CreERT2/+Rosa26tdTomato/tdTomato
- MCMV
- mouse CMV
- PT
- posttamoxifen.
- Received October 21, 2020.
- Accepted November 25, 2020.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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