NKG2D ligation relieves 2B4-mediated NK-cell self-tolerance in mice.

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-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.

• Authors: Jung Eun Lee, Seon Ah Lim, Tae-Jin Kim, Kwanghee Kim, Joanne Ng, Yong Ho Kim, In Jung Jang, Seog Bae Oh, June-Chul Lee, Cassian Yee, Vinay Kumar, Kyung-Mi Lee
• Journal: European journal of immunology (Eur J Immunol) Vol. 44 Issue 6 Pg. 1802-13 (Jun 2014) ISSN: 1521-4141 [Electronic] Germany
• PMID: 24610736 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antigens, CD
• Cd244a protein, mouse
• Klrk1 protein, mouse
• NK Cell Lectin-Like Receptor Subfamily K
• Neoplasm Proteins
• Receptors, Immunologic
• Signaling Lymphocytic Activation Molecule Family

Topics

• Animals
• Antigens, CD (genetics, immunology)
• Cell Line, Tumor
• Female
• Immunologic Capping (genetics, immunology)
• Killer Cells, Natural (immunology, pathology)
• Mice
• Mice, Knockout
• NK Cell Lectin-Like Receptor Subfamily K (genetics, immunology)
• Neoplasm Proteins (genetics, immunology)
• Neoplasms (genetics, immunology, pathology)
• Receptors, Immunologic (genetics, immunology)
• Self Tolerance
• Signaling Lymphocytic Activation Molecule Family
• Tumor Microenvironment (genetics, immunology)