Key Points
Cbl-b is induced in IL-15/IL-2/K562–activated primary human NK cells.
Abrogation of Cbl-b enhances cytotoxicity of primary human NK cells.
Abstract
The E3 ubiquitin ligase Cbl-b has been characterized as an intracellular checkpoint in T cells; however, the function of Cbl-b in primary human NK cells, an innate immune anti-tumor effector cell, is not well defined. In this study, we show that the expression of Cbl-b is significantly upregulated in primary human NK cells activated by IL-15, IL-2, and the human NK cell–sensitive tumor cell line K562 that lacks MHC class I expression. Pretreatment with JAK or AKT inhibitors prior to IL-15 stimulation reversed Cbl-b upregulation. Downregulation of Cbl-b resulted in significant increases in granzyme B and perforin expression, IFN-γ production, and cytotoxic activity against tumor cells. Collectively, we demonstrate upregulation of Cbl-b and its inhibitory effects in IL-15/IL-2/K562–activated human NK cells, suggesting that Cbl-b plays a negative feedback role in human NK cells.
Footnotes
This work was supported by grants from the Foundation for the National Institutes of Health (CA210087, CA068458, and CA163205 to M.A.C.). M.J.Y. and N.B. were supported by City of Hope’s Eugene and Ruth Roberts Summer Student Academy.
The online version of this article contains supplemental material.
- Received February 19, 2020.
- Accepted November 30, 2020.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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