Journal
BLOOD
Volume 117, Issue 16, Pages 4284-4292Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-10-316125
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Funding
- Associazione Italiana Ricerca sul Cancro [6383, 4725, 10 643, 9962]
- Ministero dell'Istruzione, Universita e Ricerca: MIUR-FIRB [RBLA039LSF-001/003]
- Ministero della Salute [3/07]
- FIRC
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In allogeneic HSCT, NK-cell alloreactivity is determined by the presence in the donor of NK cells expressing inhibitory killer cell Ig-like receptors (KIRs) that recognize HLA class I allotypes present in the donor but lacking in the recipient. Dominant KIR ligands are the C1 and C2 epitopes of HLA-C. All HLA-C allotypes have either the C1 epitope, the ligand for KIR2DL2/L3, or the C2 epitope, the ligand for KIR2DL1/S1. Here, we show that, in alloreactive NK-cell responses, KIR2DS1 expression represents a remarkable advantage as it allows efficient killing of C2/C2 or C1/C2 myelomonocitic dendritic cells (DCs) and T-cell blasts. When DCs or T-cell blasts were derived from C2/C2, Bw4/Bw4 donors, the activating signals delivered by KIR2DS1 could override the inhibition generated by NKG2A or KIR2DL2/L3 expressed on the same NK-cell clone. Furthermore, substantial lysis of C2/C2, Bw4/Bw6 targets was mediated by KIR2DS1(+) NK cells coexpressing KIR3DL1. Importantly, in the case of C1/C2 targets, KIR2DS1(+) NK cells were inhibited by the coexpression of KIR2DL2/L3 but not of NKG2A. Thus, KIR2DS1 expression in HSC donors may substantially increase the size of the alloreactive NK-cell subset leading to an enhanced ability to limit GVHD and improve engrafment. (Blood. 2011;117(16):4284-4292)
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