TY - JOUR
T1 - NKG2D ligation relieves 2B4-mediated NK-cell self-tolerance in mice
AU - Lee, Jung Eun
AU - Lim, Seon Ah
AU - Kim, Tae Jin
AU - Kim, Kwanghee
AU - Ng, Joanne
AU - Kim, Yong Ho
AU - Jang, In Jung
AU - Oh, Seog Bae
AU - Lee, June Chul
AU - Yee, Cassian
AU - Kumar, Vinay
AU - Lee, Kyung Mi
PY - 2014/6
Y1 - 2014/6
N2 - 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-1γ. In vitro cytotoxicity and in vivo peritoneal clearance assays using MHCI+CD48+ (RMA-neo), MHCI+CD48+RAE-1γ (RMA-RAE-1γ), MHCI-CD48+ (RMA-S-neo), and MHCI-CD48+RAE-1γ (RMA-S-RAE-1γ) 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-1γ, 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.
AB - 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-1γ. In vitro cytotoxicity and in vivo peritoneal clearance assays using MHCI+CD48+ (RMA-neo), MHCI+CD48+RAE-1γ (RMA-RAE-1γ), MHCI-CD48+ (RMA-S-neo), and MHCI-CD48+RAE-1γ (RMA-S-RAE-1γ) 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-1γ, 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.
KW - 2B4
KW - NKG2D
KW - Natural killer cells
KW - Self-tolerance
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U2 - 10.1002/eji.201343724
DO - 10.1002/eji.201343724
M3 - Article
C2 - 24610736
AN - SCOPUS:84899583510
VL - 44
SP - 1802
EP - 1813
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 6
ER -