NKG2D ligation relieves 2B4-mediated NK-cell self-tolerance in mice
- Authors
- Lee, Jung Eun; Lim, Seon Ah; Kim, Tae-Jin; Kim, Kwanghee; Ng, Joanne; Kim, Yong Ho; Jang, In Jung; Oh, Seog Bae; Lee, June-Chul; Yee, Cassian; Kumar, Vinay; Lee, Kyung-Mi
- Issue Date
- Jun-2014
- Publisher
- WILEY-BLACKWELL
- Keywords
- 2B4; Natural killer cells; NKG2D; self-tolerance
- Citation
- EUROPEAN JOURNAL OF IMMUNOLOGY, v.44, no.6, pp 1802 - 1813
- Pages
- 12
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- EUROPEAN JOURNAL OF IMMUNOLOGY
- Volume
- 44
- Number
- 6
- Start Page
- 1802
- End Page
- 1813
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/9279
- DOI
- 10.1002/eji.201343724
- ISSN
- 0014-2980
1521-4141
- Abstract
- Along with MHC class I (MHCI), 2B4 provides nonredundant NK-cell inhibition in mice. The immunoregulatory role of 2B4 has been increasingly appreciated in models of tumor and viral infection, however, the interactions among 2B4, MHCI, and other activating NK-cell receptors remain uncertain. Here, we dissect the influence of two distinct inhibitory pathways in modulating NK-cell-mediated control of tumors expressing strong activating ligands, including RAE-1. In vitro cytotoxicity and in vivo peritoneal clearance assays using MHCI+CD48+ (RMA-neo), MHCI+CD48+RAE-1 (RMA-RAE-1), MHCI-CD48+ (RMA-S-neo), and MHCI-CD48+RAE-1 (RMA-S-RAE-1) tumor lines demonstrated that NKG2D activation supersedes the inhibitory effect of both 2B4- and MHCI-mediated immune-tolerance systems. Furthermore, 2B4KO mice subcutaneously challenged with RMA-neo and RMA-S-neo exhibited reduced tumor growth and significantly prolonged survival compared with WT mice, implying that 2B4 is constitutively engaged in the NK-cell tolerance mechanism in vivo. Nevertheless, the inhibitory effect of 2B4 is significantly attenuated when NK cells encountered highly stressed tumor cells expressing RAE-1, resulting in an immune response shift toward NK-cell activation and tumor regression. Therefore, our data highlight the importance of the 2B4-mediated inhibitory system as an alternate self-tolerance mechanism, whose role can be modulated by the strength of activating receptor signaling within the tumor microenvironment.
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- Appears in
Collections - 1. Basic Science > Department of Biochemistry and Molecular Biology > 1. Journal Articles
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