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The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation.

Isernhagen A, Malzahn D, Viktorova E, Elsner L, Monecke S, von Bonin F, Kilisch M, Wermuth JM, Walther N, Balavarca Y, Stahl-Hennig C, Engelke M, Walter L, Bickeböller H, Kube D, Wulf G, Dressel R - EMBO Mol Med (2015)

Bottom Line: A single nucleotide polymorphism causes a valine to methionine exchange at position 129.Functionally, the MICA-129Met isoform was characterized by stronger NKG2D signaling, triggering more NK-cell cytotoxicity and interferon-γ release, and faster co-stimulation of CD8(+) T cells.The MICA-129Met variant also induced a faster and stronger down-regulation of NKG2D on NK and CD8(+) T cells than the MICA-129Val isoform.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.

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Down-regulation of NGK2D on CD56dimCD16+, CD56brightCD16+, and CD56brightCD16− NK cells in response to the MICA-129Met and the MICA-129Val isoformsPurified IL-2-stiumlated NK cells (100 U/ml for 4 days) were co-cultured with L-con, L-MICA-129Met, or L-MICA-129Val clones for 4 h. Three NK-cell populations (CD56dimCD16+, CD56brightCD16+, CD56brightCD16−) were gated as illustrated in the upper panel. The NKG2D expression on these NK-cell populations is displayed in the lower panel, and the MFI of NKG2D and the percentages of NKG2D+ cells are indicated.A summary (means + SD) of NKG2D expression on the three NK-cell populations 4 and 24 h after co-culture with L-con (n = 3), L-MICA-129Met (n = 17), and L-MICA-129Val clones (n = 18) is displayed. The NKG2D expression (MFI) at the beginning (0 h) was set to 100%. The average reduction of NKG2D on NK cells in response to L-MICA-129Met compared to L-MICA-129Val clones at 4 and 24 h (%-points) is indicated in the panels. The differences were analyzed by repeated measures ANOVA, and P-values are indicated.
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fig12ev: Down-regulation of NGK2D on CD56dimCD16+, CD56brightCD16+, and CD56brightCD16− NK cells in response to the MICA-129Met and the MICA-129Val isoformsPurified IL-2-stiumlated NK cells (100 U/ml for 4 days) were co-cultured with L-con, L-MICA-129Met, or L-MICA-129Val clones for 4 h. Three NK-cell populations (CD56dimCD16+, CD56brightCD16+, CD56brightCD16−) were gated as illustrated in the upper panel. The NKG2D expression on these NK-cell populations is displayed in the lower panel, and the MFI of NKG2D and the percentages of NKG2D+ cells are indicated.A summary (means + SD) of NKG2D expression on the three NK-cell populations 4 and 24 h after co-culture with L-con (n = 3), L-MICA-129Met (n = 17), and L-MICA-129Val clones (n = 18) is displayed. The NKG2D expression (MFI) at the beginning (0 h) was set to 100%. The average reduction of NKG2D on NK cells in response to L-MICA-129Met compared to L-MICA-129Val clones at 4 and 24 h (%-points) is indicated in the panels. The differences were analyzed by repeated measures ANOVA, and P-values are indicated.

Mentions: Notably, the NKG2D expression was significantly reduced on all three NK-cell subpopulations 4 and 24 h after exposure to MICA-expressing targets (FigEV4A). After adjustment to MICA expression intensities, the NKG2D expression was on average 19.5 (P = 8.04 × 10−6, CD56dimCD16+), 16.2 (P = 2.26 × 10−8, CD56brightCD16+), or 15.8%-points (P = 1.02 × 10−4, CD56brightCD16−) lower on NK cells exposed to L-MICA-129Met than L-MICA-129Val clones (FigEV4B). Hence, the MICA-129Met variant induced a stronger down-regulation of NKG2D than the MICA-129Val variant. This counter-regulation appears to limit the initially stronger functional effects of the MICA-129Met variant on NKG2D signaling.


The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation.

Isernhagen A, Malzahn D, Viktorova E, Elsner L, Monecke S, von Bonin F, Kilisch M, Wermuth JM, Walther N, Balavarca Y, Stahl-Hennig C, Engelke M, Walter L, Bickeböller H, Kube D, Wulf G, Dressel R - EMBO Mol Med (2015)

Down-regulation of NGK2D on CD56dimCD16+, CD56brightCD16+, and CD56brightCD16− NK cells in response to the MICA-129Met and the MICA-129Val isoformsPurified IL-2-stiumlated NK cells (100 U/ml for 4 days) were co-cultured with L-con, L-MICA-129Met, or L-MICA-129Val clones for 4 h. Three NK-cell populations (CD56dimCD16+, CD56brightCD16+, CD56brightCD16−) were gated as illustrated in the upper panel. The NKG2D expression on these NK-cell populations is displayed in the lower panel, and the MFI of NKG2D and the percentages of NKG2D+ cells are indicated.A summary (means + SD) of NKG2D expression on the three NK-cell populations 4 and 24 h after co-culture with L-con (n = 3), L-MICA-129Met (n = 17), and L-MICA-129Val clones (n = 18) is displayed. The NKG2D expression (MFI) at the beginning (0 h) was set to 100%. The average reduction of NKG2D on NK cells in response to L-MICA-129Met compared to L-MICA-129Val clones at 4 and 24 h (%-points) is indicated in the panels. The differences were analyzed by repeated measures ANOVA, and P-values are indicated.
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Related In: Results  -  Collection

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fig12ev: Down-regulation of NGK2D on CD56dimCD16+, CD56brightCD16+, and CD56brightCD16− NK cells in response to the MICA-129Met and the MICA-129Val isoformsPurified IL-2-stiumlated NK cells (100 U/ml for 4 days) were co-cultured with L-con, L-MICA-129Met, or L-MICA-129Val clones for 4 h. Three NK-cell populations (CD56dimCD16+, CD56brightCD16+, CD56brightCD16−) were gated as illustrated in the upper panel. The NKG2D expression on these NK-cell populations is displayed in the lower panel, and the MFI of NKG2D and the percentages of NKG2D+ cells are indicated.A summary (means + SD) of NKG2D expression on the three NK-cell populations 4 and 24 h after co-culture with L-con (n = 3), L-MICA-129Met (n = 17), and L-MICA-129Val clones (n = 18) is displayed. The NKG2D expression (MFI) at the beginning (0 h) was set to 100%. The average reduction of NKG2D on NK cells in response to L-MICA-129Met compared to L-MICA-129Val clones at 4 and 24 h (%-points) is indicated in the panels. The differences were analyzed by repeated measures ANOVA, and P-values are indicated.
Mentions: Notably, the NKG2D expression was significantly reduced on all three NK-cell subpopulations 4 and 24 h after exposure to MICA-expressing targets (FigEV4A). After adjustment to MICA expression intensities, the NKG2D expression was on average 19.5 (P = 8.04 × 10−6, CD56dimCD16+), 16.2 (P = 2.26 × 10−8, CD56brightCD16+), or 15.8%-points (P = 1.02 × 10−4, CD56brightCD16−) lower on NK cells exposed to L-MICA-129Met than L-MICA-129Val clones (FigEV4B). Hence, the MICA-129Met variant induced a stronger down-regulation of NKG2D than the MICA-129Val variant. This counter-regulation appears to limit the initially stronger functional effects of the MICA-129Met variant on NKG2D signaling.

Bottom Line: A single nucleotide polymorphism causes a valine to methionine exchange at position 129.Functionally, the MICA-129Met isoform was characterized by stronger NKG2D signaling, triggering more NK-cell cytotoxicity and interferon-γ release, and faster co-stimulation of CD8(+) T cells.The MICA-129Met variant also induced a faster and stronger down-regulation of NKG2D on NK and CD8(+) T cells than the MICA-129Val isoform.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.

Show MeSH
Related in: MedlinePlus