Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2010 May;235(1):267-85.
doi: 10.1111/j.0105-2896.2010.00893.x.

Effect of NKG2D ligand expression on host immune responses

Marine Champsaur  1 , Lewis L Lanier
Affiliations
Review

Effect of NKG2D ligand expression on host immune responses

Marine Champsaur et al. Immunol Rev. 2010 May.

Abstract

Natural killer group 2, member D (NKG2D) is an activating receptor present on the surface of natural killer (NK) cells, some NKT cells, CD8(+) cytotoxic T cells, gammadelta T cells, and under certain conditions CD4(+) T cells. Present in both humans and mice, this highly conserved receptor binds to a surprisingly diverse family of ligands that are distant relatives of major histocompatibility complex class I molecules. There is increasing evidence that ligand expression can result in both immune activation (tumor clearance, viral immunity, autoimmunity, and transplantation) and immune silencing (tumor evasion). In this review, we describe this family of NKG2D ligands and the various mechanisms that control their expression in stressed and normal cells. We also discuss the host response to both membrane-bound and secreted NKG2D ligands and summarize the models proposed to explain the consequences of this differential expression.

PubMed Disclaimer

Figures

Fig 1
Fig 1. Schematic representation of the NKG2D receptor complex
NKG2D is a type-2 transmembrane homodimer that signals via association with adapter molecules through charged residues in the transmembrane domain. Mouse NKG2D associates with both DAP10 and DAP12 signaling molecules, whereas human NKG2D associates with DAP10 only. Pairing with DAP12 results in the phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) and triggering of the Syk and/or Zap70 cascade. Association with DAP10 leads to tyrosine phosphorylation on the YINM motif and triggering of the PI3K and Grb2 signaling cascade.
Fig 2
Fig 2. Structures and affinities of mouse and human NKG2D ligands
(A) MHC class-I-chain-related protein A (MICA) and MICB are the only ligands known to date to contain an α3-like domain. All other ligands contain only α1 and α2 domains. Both mouse and human NKG2D ligands can be either transmembrane-anchored proteins (shown in blue rectangle) or glycosylphosphatidylinositol (GPI)- anchored (shown in red). (B) The affinities are expressed as the equilibrium dissociation constant (KD) and given for interactions between NKG2D receptor and ligands of the same species. Mouse NKG2D binds some human ligands (at lower affinity than mouse ligands), but human NKG2D does not bind mouse ligands.
Fig. 3
Fig. 3. NKG2D ligands can be secreted from tumor cell lines and Rae-1 Tg mice
(A, B) Supernatant harvested from (A) B16 (black line) or Rae-1ε-transduced melanoma tumor cells (red line) or (B) RMA (black line) or Rae-1ε-transduced (red line) lymphoma cells was incubated with mouse NKG2D-Ig (mNKG2D-Ig) for 30 min on ice. This mixture was then used to stain MICA-transduced BaF/3 cell transfectants on ice for 30 min. A secondary goat anti-human IgG antibody was used to measure binding of mNKG2D-Ig to the transfectants. Controls included cells stained with control human Ig (grey filling) and cells stained with mNKG2D-Ig pre-incubated with soluble MULT1-secreting transfectants (dashed line). (C) Serum from Rae-1 Tg or littermate control mice was incubated with mNKG2D-Ig for 30 min on ice. This mixture was then used to stain MICA-BaF/3 cell transfectants on ice for 30 min. A secondary goat anti-human IgG antibody was used to measure binding of mNKG2D-Ig to the transfectants. Mean fluorescence intensity (MFI) of mNKG2D-Ig binding to MICA-BaF/3 cells is shown following incubation with WT or Rae-1 Tg sera.
Fig. 4
Fig. 4. Soluble MULT1 construct is efficiently secreted and downregulates NKG2D on splenocytes
(A) A soluble MULT1 (sMULT1) construct was created by inserting a STOP codon at a site between the extracellular domain and the transmembrane domain of full-length MULT1 (FL MULT1) and cloning the PCR product into pEF-bOS vector. Constructs encoding sMULT1 or FL MULT1 were transfected into 293T cells. 48 h post-transfection, supernatant from sMULT1 or FL MULT1 transfectants was collected. (B) sMULT1(red line) or FL MULT1(blue line) supernatant was incubated with 10 μg/mL of mNKG2D-Ig for 30 min on ice. This mixture was then used to stain MICA-BaF/3 cell transfectants. Control human Ig staining is shown (grey filling). (C) sMULT1 (right plot) or FL MULT1(left plot) supernatant was added to splenocytes overnight. NKG2D expression on NK cells was detected by using anti-NKG2D (CX5) antibody. (D) Mouse NKG2D-transfected BaF/3 cells were incubated with supernatant from untransfected 293T cells or 293T cells transfected with sMULT-1 or FL MULT1. After 5 h, cells were spun and acid-washed (pH=2.5) for 1.5 and 5 min. Cells were then washed and stained with anti-NKG2D (CX5) and anti-NK1.1 to detect NK cells.
Fig. 5
Fig. 5. Soluble MULT1 impairment of NKG2D cytotoxicity is reversed by the addition of an anti-MULT1 antibody
(A–C) NK cells were isolated from spleen by removing CD4+ and CD8+ cells using antibody-coated magnetic beads, and then positively selecting for DX5+ cells. Cells were grown in IL-2-containing medium (4000 IU/ml IL-2) for 5 days. (A) On day 5, NK cells were harvested, incubated with FL MULT1 (solid line) or sMULT1 (dashed line) - containing supernatant for 2 h and then used in a standard 51Cr release assay against various NKG2D-ligand bearing target cells. MICA-BaF/3 (blue line), MULT1-BaF/3 (green line), and Rae1-BaF/3 (red line) cells were blocked to varying degree by the addition of sMULT1. (B) Blocking effect of sMULT1 is proportional to the amount of ligand detected on the cell surface of targets, and measured by staining with mNKG2D-Ig. (C) NK cells cultured in IL-2 for 5 days were incubated with FL MULT1 (blue line), sMULT1 alone (red line), or sMULT1 in the presence of 20 μ/ml anti-MULT1 antibody (green line) for 2 h. NK cells were then used in a standard 51Cr release assay against various NKG2D-ligand bearing target cells. Black line shows background killing of untransfected BaF/3 parental cells.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23:225–74. - PubMed
    1. Ljunggren H-G, Kärre K. In search of the “missing self”: MHC molecules and NK cell recognition. Immunology Today. 1990;11:237–44. - PubMed
    1. Guerra N, et al. NKG2D-Deficient Mice Are Defective in Tumor Surveillance in Models of Spontaneous Malignancy. 2008;28:571–80. - PMC - PubMed
    1. Zafirova B, et al. Altered NK Cell Development and Enhanced NK Cell-Mediated Resistance to Mouse Cytomegalovirus in NKG2D-Deficient Mice. 2009;31:270–82. - PMC - PubMed
    1. Houchins JP, Yabe T, McSherry C, Bach FH. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J Exp Med. 1991;173:1017–20. - PMC - PubMed

Publication types

MeSH terms

Substances