Abstract
KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E35) are functionally stronger than those with glutamine at the same position (Q35). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E35 could kill more target cells lacking their ligands than NK cells with the weaker -Q35 alleles, indicating better licensing of KIR2DL2/L3+ NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.
Highlights
Killer cell immunoglobulin-like receptors (KIRs) are expressed on the surface of most NK cells and a subset of T-cells[1,2]
KIR genes are highly polymorphic in nature exhibiting haplotypic and allelic variations[8,18]
For example a study by Moesta et al reported that positions 16 and 148 accounted for KIR2DL2*001 being a stronger receptor for HLA-C ligand than KIR2DL3*0019
Summary
Killer cell immunoglobulin-like receptors (KIRs) are expressed on the surface of most NK cells and a subset of T-cells[1,2]. We have shown previously that KIR2DL1 alleles with arginine in position 245 of the transmembrane domain (KIR2DL1-R245) are stronger than those with cysteine (KIR2DL1-C245)[11]. The molecular determinants of KIR2DL2/L3 functional diversity have not been elucidated, Frazier et al have shown differential affinity and avidity of some common KIR2DL2 and KIR2DL3 alleles toward their HLA-C ligands, using Surface Plasmon Resonance (SPR)[14]. Three KIR2DL2 alleles (*001, *003 and *006) showed higher ligand affinity and avidity when compared to two other KIR2DL3 alleles (*001 and *002) that had glutamine at amino acid position 35 (Q35). One KIR2DL3 family member (*005) that contains glutamic acid at the same position (E35) showed high affinity and avidity toward HLA-C ligand at a level similar to those of KIR2DL2 alleles[14]. We investigated whether position 35 could be a useful biomarker to distinguish stronger versus weaker KIR2DL2/L3 for clinical uses
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