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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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IFNγ production of NK cells in response to the MICA-129Met and MICA-129Val isoformsThe IFNγ expression of purified IL-2-stimulated (100 U/ml for 4 days) NK cells exposed for 4 h to L-MICA-129Met (n = 23) or L-MICA-129Val clones (n = 23) was determined by flow cytometry. The IFNγ expression was analyzed after gating on CD56brightCD16− NK cells. In parallel, the MICA expression on target cells was determined. Displayed are the linear regressions of the MFI of IFNγ in CD56brightCD16− NK cells (upper panels) or the proportion of IFNγ+ CD56brightCD16− NK cells (lower panels) and the MICA expression intensity on target cells (MFI) for the L-MICA-129Met (left panels) and L-MICA-129Val clones (right panels). The coefficients of determination (R2), the regression coefficients (reg. coeff.), and the P-values for Pearson correlation are indicated.The IFNγ release of purified IL-2-stimulated NK cells (100 U/ml for 4 days) co-cultured with L-MICA-129Met (n = 34) or L-MICA-129Val clones (n = 32) for 24 h was measured in the supernatant by ELISA. In parallel, the MICA expression intensity on target cells was determined by flow cytometry. The linear regressions of IFNγ release (pg/ml) by NK cells and MICA expression on targets (MFI) are displayed for the L-MICA-129Met clones (left panel) and the L-MICA-129Val clones (right panel). The coefficients of determination (R2), the regression coefficients (reg. coeff.), and the P-values for Pearson correlation are indicated.
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fig04: IFNγ production of NK cells in response to the MICA-129Met and MICA-129Val isoformsThe IFNγ expression of purified IL-2-stimulated (100 U/ml for 4 days) NK cells exposed for 4 h to L-MICA-129Met (n = 23) or L-MICA-129Val clones (n = 23) was determined by flow cytometry. The IFNγ expression was analyzed after gating on CD56brightCD16− NK cells. In parallel, the MICA expression on target cells was determined. Displayed are the linear regressions of the MFI of IFNγ in CD56brightCD16− NK cells (upper panels) or the proportion of IFNγ+ CD56brightCD16− NK cells (lower panels) and the MICA expression intensity on target cells (MFI) for the L-MICA-129Met (left panels) and L-MICA-129Val clones (right panels). The coefficients of determination (R2), the regression coefficients (reg. coeff.), and the P-values for Pearson correlation are indicated.The IFNγ release of purified IL-2-stimulated NK cells (100 U/ml for 4 days) co-cultured with L-MICA-129Met (n = 34) or L-MICA-129Val clones (n = 32) for 24 h was measured in the supernatant by ELISA. In parallel, the MICA expression intensity on target cells was determined by flow cytometry. The linear regressions of IFNγ release (pg/ml) by NK cells and MICA expression on targets (MFI) are displayed for the L-MICA-129Met clones (left panel) and the L-MICA-129Val clones (right panel). The coefficients of determination (R2), the regression coefficients (reg. coeff.), and the P-values for Pearson correlation are indicated.

Mentions: Next, we exposed NK cells to MICA-expressing L cells. After adjustment to MICA expression intensity on different clones, CD56brightCD16− NK cells co-cultured with L-MICA-129Val targets expressed less IFNγ compared to cells exposed to MICA-129Met clones. The MFI of IFNγ was on average 12.5 units lower (P = 0.0032, ANCOVA), and 7.5%-points less CD56brightCD16− NK cells were IFNγ positive (P = 0.0061, ANCOVA). For CD56brightCD16− NK cells encountering the MICA-129Val variant, the proportion of IFNγ+ cells and the MFI of IFNγ increased with MICA expression intensity (regression coefficients 0.14 and 0.09, respectively), whereas cells exposed to the MICA-129Met variant expressed less IFNγ when co-cultured with targets with higher MICA expression intensity (MFI, regression coefficient −1.11; Fig4A). The results obtained for CD56brightCD16+ and CD56dimCD16+ NK cells in these experiments are shown in the Appendix Fig S7.


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)

IFNγ production of NK cells in response to the MICA-129Met and MICA-129Val isoformsThe IFNγ expression of purified IL-2-stimulated (100 U/ml for 4 days) NK cells exposed for 4 h to L-MICA-129Met (n = 23) or L-MICA-129Val clones (n = 23) was determined by flow cytometry. The IFNγ expression was analyzed after gating on CD56brightCD16− NK cells. In parallel, the MICA expression on target cells was determined. Displayed are the linear regressions of the MFI of IFNγ in CD56brightCD16− NK cells (upper panels) or the proportion of IFNγ+ CD56brightCD16− NK cells (lower panels) and the MICA expression intensity on target cells (MFI) for the L-MICA-129Met (left panels) and L-MICA-129Val clones (right panels). The coefficients of determination (R2), the regression coefficients (reg. coeff.), and the P-values for Pearson correlation are indicated.The IFNγ release of purified IL-2-stimulated NK cells (100 U/ml for 4 days) co-cultured with L-MICA-129Met (n = 34) or L-MICA-129Val clones (n = 32) for 24 h was measured in the supernatant by ELISA. In parallel, the MICA expression intensity on target cells was determined by flow cytometry. The linear regressions of IFNγ release (pg/ml) by NK cells and MICA expression on targets (MFI) are displayed for the L-MICA-129Met clones (left panel) and the L-MICA-129Val clones (right panel). The coefficients of determination (R2), the regression coefficients (reg. coeff.), and the P-values for Pearson correlation are indicated.
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Related In: Results  -  Collection

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fig04: IFNγ production of NK cells in response to the MICA-129Met and MICA-129Val isoformsThe IFNγ expression of purified IL-2-stimulated (100 U/ml for 4 days) NK cells exposed for 4 h to L-MICA-129Met (n = 23) or L-MICA-129Val clones (n = 23) was determined by flow cytometry. The IFNγ expression was analyzed after gating on CD56brightCD16− NK cells. In parallel, the MICA expression on target cells was determined. Displayed are the linear regressions of the MFI of IFNγ in CD56brightCD16− NK cells (upper panels) or the proportion of IFNγ+ CD56brightCD16− NK cells (lower panels) and the MICA expression intensity on target cells (MFI) for the L-MICA-129Met (left panels) and L-MICA-129Val clones (right panels). The coefficients of determination (R2), the regression coefficients (reg. coeff.), and the P-values for Pearson correlation are indicated.The IFNγ release of purified IL-2-stimulated NK cells (100 U/ml for 4 days) co-cultured with L-MICA-129Met (n = 34) or L-MICA-129Val clones (n = 32) for 24 h was measured in the supernatant by ELISA. In parallel, the MICA expression intensity on target cells was determined by flow cytometry. The linear regressions of IFNγ release (pg/ml) by NK cells and MICA expression on targets (MFI) are displayed for the L-MICA-129Met clones (left panel) and the L-MICA-129Val clones (right panel). The coefficients of determination (R2), the regression coefficients (reg. coeff.), and the P-values for Pearson correlation are indicated.
Mentions: Next, we exposed NK cells to MICA-expressing L cells. After adjustment to MICA expression intensity on different clones, CD56brightCD16− NK cells co-cultured with L-MICA-129Val targets expressed less IFNγ compared to cells exposed to MICA-129Met clones. The MFI of IFNγ was on average 12.5 units lower (P = 0.0032, ANCOVA), and 7.5%-points less CD56brightCD16− NK cells were IFNγ positive (P = 0.0061, ANCOVA). For CD56brightCD16− NK cells encountering the MICA-129Val variant, the proportion of IFNγ+ cells and the MFI of IFNγ increased with MICA expression intensity (regression coefficients 0.14 and 0.09, respectively), whereas cells exposed to the MICA-129Met variant expressed less IFNγ when co-cultured with targets with higher MICA expression intensity (MFI, regression coefficient −1.11; Fig4A). The results obtained for CD56brightCD16+ and CD56dimCD16+ NK cells in these experiments are shown in the Appendix Fig S7.

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