Cbl-b Is Upregulated and Plays a Negative Role in Activated Human NK Cells

• Published in: The Journal of immunology (1950) Vol. 206; no. 4; pp. 677 - 685
• Main Authors: Lu, Ting, Chen, Li, Mansour, Anthony G, Yu, Melissa J, Brooks, Noah, Teng, Kun-Yu, Li, Zhenlong, Zhang, Jianying, Barr, Tasha, Yu, Jianhua, Caligiuri, Michael A
• Format: Journal Article
• Language: English
• Published: United States 15.02.2021
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Cytotoxicity, Immunologic; Granzymes - genetics; Granzymes - metabolism; Humans; Immune Checkpoint Proteins - genetics; Immune Checkpoint Proteins - metabolism; Immunity, Innate; Interferon-gamma - metabolism; Interleukin-15 - metabolism; Interleukin-2 - metabolism; K562 Cells; Killer Cells, Natural - immunology; Lymphocyte Activation; Perforin - genetics; Perforin - metabolism; Proto-Oncogene Proteins c-cbl - genetics; Proto-Oncogene Proteins c-cbl - metabolism; Signal Transduction; Up-Regulation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2000177

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.