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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 CD8+ T cells in response to the MICA-129Met and MICA-129Val isoformsPurified CD8+ T cells were analyzed by flow cytometry for NKG2D expression as illustrated here. The MFI for NKG2D and the percentage of NKG2D+CD8+ T cells are indicated.The NK cells were subsequently co-cultured with an L-con, L-MICA-129Met, or L-MICA-129Val clone (the MFI values for MICA on these clones are indicated above the histograms in brackets). NKG2D expression was determined as illustrated in (A) after 4 and 24 h. The MFI for NKG2D and the percentages of NKG2D+CD8+ T cells are indicated.
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fig13ev: Down-regulation of NGK2D on CD8+ T cells in response to the MICA-129Met and MICA-129Val isoformsPurified CD8+ T cells were analyzed by flow cytometry for NKG2D expression as illustrated here. The MFI for NKG2D and the percentage of NKG2D+CD8+ T cells are indicated.The NK cells were subsequently co-cultured with an L-con, L-MICA-129Met, or L-MICA-129Val clone (the MFI values for MICA on these clones are indicated above the histograms in brackets). NKG2D expression was determined as illustrated in (A) after 4 and 24 h. The MFI for NKG2D and the percentages of NKG2D+CD8+ T cells are indicated.

Mentions: NKG2D was strongly down-regulated on CD8+ T cells co-cultured with L-MICA-129Met but hardly after co-culture with L-MICA-129Val clones (FigEV5). The proportion of NKG2D+CD3+CD8+ cells decreased by 35.8%-points more when exposed to L-MICA-129Met clones compared to those encountering the L-MICA-129Val clones (P = 7.8 × 10−8 two-way ANOVA adjusted for MICA expression intensity on different clones), and the MFI of NKG2D decreased by 12.1 units more (P = 2.6 × 10−5; Fig7A). Notably, on CD8+ T cells, the MFI of NKG2D decreased clearly more when exposed to clones with higher MICA-129Met expression intensity (P = 0.016, two-way ANCOVA), whereas CD8 expression was not altered indicating the specificity of the effect (Appendix Fig S13). The down-regulation of NGK2D on CD8+ T cells was functionally relevant. Exposure of CD8+ T cells to anti-NKG2D for 24 h reduced NKG2D expression (Fig7B) and impaired their capability to proliferate subsequently in response to NKG2D-mediated co-stimulation (Fig7C and D and Appendix Fig S14). The strong down-regulation of NKG2D on CD8+ T cells by MICA-129Met variants appears to be important for the association of this polymorphism with the outcome of HSCT.


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 CD8+ T cells in response to the MICA-129Met and MICA-129Val isoformsPurified CD8+ T cells were analyzed by flow cytometry for NKG2D expression as illustrated here. The MFI for NKG2D and the percentage of NKG2D+CD8+ T cells are indicated.The NK cells were subsequently co-cultured with an L-con, L-MICA-129Met, or L-MICA-129Val clone (the MFI values for MICA on these clones are indicated above the histograms in brackets). NKG2D expression was determined as illustrated in (A) after 4 and 24 h. The MFI for NKG2D and the percentages of NKG2D+CD8+ T cells are indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644379&req=5

fig13ev: Down-regulation of NGK2D on CD8+ T cells in response to the MICA-129Met and MICA-129Val isoformsPurified CD8+ T cells were analyzed by flow cytometry for NKG2D expression as illustrated here. The MFI for NKG2D and the percentage of NKG2D+CD8+ T cells are indicated.The NK cells were subsequently co-cultured with an L-con, L-MICA-129Met, or L-MICA-129Val clone (the MFI values for MICA on these clones are indicated above the histograms in brackets). NKG2D expression was determined as illustrated in (A) after 4 and 24 h. The MFI for NKG2D and the percentages of NKG2D+CD8+ T cells are indicated.
Mentions: NKG2D was strongly down-regulated on CD8+ T cells co-cultured with L-MICA-129Met but hardly after co-culture with L-MICA-129Val clones (FigEV5). The proportion of NKG2D+CD3+CD8+ cells decreased by 35.8%-points more when exposed to L-MICA-129Met clones compared to those encountering the L-MICA-129Val clones (P = 7.8 × 10−8 two-way ANOVA adjusted for MICA expression intensity on different clones), and the MFI of NKG2D decreased by 12.1 units more (P = 2.6 × 10−5; Fig7A). Notably, on CD8+ T cells, the MFI of NKG2D decreased clearly more when exposed to clones with higher MICA-129Met expression intensity (P = 0.016, two-way ANCOVA), whereas CD8 expression was not altered indicating the specificity of the effect (Appendix Fig S13). The down-regulation of NGK2D on CD8+ T cells was functionally relevant. Exposure of CD8+ T cells to anti-NKG2D for 24 h reduced NKG2D expression (Fig7B) and impaired their capability to proliferate subsequently in response to NKG2D-mediated co-stimulation (Fig7C and D and Appendix Fig S14). The strong down-regulation of NKG2D on CD8+ T cells by MICA-129Met variants appears to be important for the association of this polymorphism with the outcome of HSCT.

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