The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation.
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.
Affiliation: Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.Show MeSH
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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.
Affiliation: Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.