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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 NKG2D on NK cells in response to the MICA-129Met and MICA-129Val isoformsNKG2D expression on purified IL-2-stimulated NK cells (100 U/ml for 4 days) exposed to L-MICA-129Met (n = 25) or L-MICA-129Val clones (n = 25) for 0, 4, and 24 h was analyzed by flow cytometry. NK cells (2.5 × 105) were co-cultured with 5 × 104 target cells and analyzed for NKG2D expression after gating of CD3−CD56+ cells. The means and SD of the percentage of NKG2D+ NK cells (left panel) and of the MFI of NKG2D (right panel) are shown. Differences between the groups were analyzed by repeated measures ANOVA, and P-values for pairwise comparisons are indicated.
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fig05: Down-regulation of NKG2D on NK cells in response to the MICA-129Met and MICA-129Val isoformsNKG2D expression on purified IL-2-stimulated NK cells (100 U/ml for 4 days) exposed to L-MICA-129Met (n = 25) or L-MICA-129Val clones (n = 25) for 0, 4, and 24 h was analyzed by flow cytometry. NK cells (2.5 × 105) were co-cultured with 5 × 104 target cells and analyzed for NKG2D expression after gating of CD3−CD56+ cells. The means and SD of the percentage of NKG2D+ NK cells (left panel) and of the MFI of NKG2D (right panel) are shown. Differences between the groups were analyzed by repeated measures ANOVA, and P-values for pairwise comparisons are indicated.

Mentions: Sustained exposure of NK cells to NKG2D ligand-expressing cells can also down-regulate NKG2D (Coudert et al, 2005; Ogasawara et al, 2005; Oppenheim et al, 2005; Wiemann et al, 2005). Thus, we investigated NKG2D expression on NK cells exposed for 4 and 24 h to L-con, L-MICA-129Met, or L-MICA-129Val clones (Fig5, Appendix Fig S9A). The percentage of NKG2D+ NK cells decreased by 9.5%-points for the MICA-129Val (P = 0.0309) and by 19.4%-points for the MICA-129Met variant (P < 0.0001) compared to the control (co-culture with L-con cells; two-way ANCOVA adjusted for MICA expression intensity on different clones). The MFI of NKG2D decreased by 11.8 units for the MICA-129Val (P = 0.0006) and by 13.7 units for the MICA-129Met variant (P = 0.0001) compared to the control (two-way ANCOVA). Notably, the percentage of NKG2D+ cells decreased more among NK cells encountering L-MICA-129Met than L-MICA-129Val targets (−9.3%-points, P = 0.0008, two-way ANCOVA). In addition, the MFI of NKG2D was significantly different between NK cells exposed to L-MICA-129Met and L-MICA-129Val targets (P = 0.0225, two-way ANCOVA). In these analyses as in the previous analyses, we adjusted for the MICA expression intensity on different clones although it had little effect on the NKG2D down-regulation on NK cells (Appendix Fig S10). NK cells co-cultured with L-MICA cells did not show differences in CD94 expression indicating the specificity of the effect (Appendix Fig S9B and C).


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 NKG2D on NK cells in response to the MICA-129Met and MICA-129Val isoformsNKG2D expression on purified IL-2-stimulated NK cells (100 U/ml for 4 days) exposed to L-MICA-129Met (n = 25) or L-MICA-129Val clones (n = 25) for 0, 4, and 24 h was analyzed by flow cytometry. NK cells (2.5 × 105) were co-cultured with 5 × 104 target cells and analyzed for NKG2D expression after gating of CD3−CD56+ cells. The means and SD of the percentage of NKG2D+ NK cells (left panel) and of the MFI of NKG2D (right panel) are shown. Differences between the groups were analyzed by repeated measures ANOVA, and P-values for pairwise comparisons are indicated.
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Related In: Results  -  Collection

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fig05: Down-regulation of NKG2D on NK cells in response to the MICA-129Met and MICA-129Val isoformsNKG2D expression on purified IL-2-stimulated NK cells (100 U/ml for 4 days) exposed to L-MICA-129Met (n = 25) or L-MICA-129Val clones (n = 25) for 0, 4, and 24 h was analyzed by flow cytometry. NK cells (2.5 × 105) were co-cultured with 5 × 104 target cells and analyzed for NKG2D expression after gating of CD3−CD56+ cells. The means and SD of the percentage of NKG2D+ NK cells (left panel) and of the MFI of NKG2D (right panel) are shown. Differences between the groups were analyzed by repeated measures ANOVA, and P-values for pairwise comparisons are indicated.
Mentions: Sustained exposure of NK cells to NKG2D ligand-expressing cells can also down-regulate NKG2D (Coudert et al, 2005; Ogasawara et al, 2005; Oppenheim et al, 2005; Wiemann et al, 2005). Thus, we investigated NKG2D expression on NK cells exposed for 4 and 24 h to L-con, L-MICA-129Met, or L-MICA-129Val clones (Fig5, Appendix Fig S9A). The percentage of NKG2D+ NK cells decreased by 9.5%-points for the MICA-129Val (P = 0.0309) and by 19.4%-points for the MICA-129Met variant (P < 0.0001) compared to the control (co-culture with L-con cells; two-way ANCOVA adjusted for MICA expression intensity on different clones). The MFI of NKG2D decreased by 11.8 units for the MICA-129Val (P = 0.0006) and by 13.7 units for the MICA-129Met variant (P = 0.0001) compared to the control (two-way ANCOVA). Notably, the percentage of NKG2D+ cells decreased more among NK cells encountering L-MICA-129Met than L-MICA-129Val targets (−9.3%-points, P = 0.0008, two-way ANCOVA). In addition, the MFI of NKG2D was significantly different between NK cells exposed to L-MICA-129Met and L-MICA-129Val targets (P = 0.0225, two-way ANCOVA). In these analyses as in the previous analyses, we adjusted for the MICA expression intensity on different clones although it had little effect on the NKG2D down-regulation on NK cells (Appendix Fig S10). NK cells co-cultured with L-MICA cells did not show differences in CD94 expression indicating the specificity of the effect (Appendix Fig S9B and C).

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