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