The Journal of Immunology, 2007, 178: 35.17.
Copyright © 2007 by The American Association of Immunologists, Inc.
KIR/HLA Compound Genotypes Determine Early Antiviral Response of Natural Killer Cells
Golo Ahlenstiel1,
Maureen P Martin2,
Xiaojiang Gao2,
Mary Carrington2 and
Barbara Rehermann1
1 Immunology Section, LDB, NIDDK, NIH, DHHS, 10 Center Drive, Bldg. 10, Room 9B11, Bethesda, MD, 20892-1800,
2 Laboratory of Genomic Diversity, SAIC-Frederick, Inc., NCI-Frederick, 1050 Boyles Street, Bldg. 560, Room 21-89, Frederick, MD, 21702-1201
Abstract
A growing number of genetic epidemiological studies have suggested an influence of the extraordinarily polymorphic KIR/HLA compound genotypes in determining outcome to viral infections, but functional data to explain these genetic data have not been reported to date. Using an in vitro influenza A virus infection model, we here attribute functional differences in human NK cell activity to distinct KIR/HLA genotypes. Using cytokine EIAs and multicolor flow cytometry, we show that NK cells from KIR2DL3+/KIR2DL1+ and HLA-C1 homozygous subjects display a faster response kinetics and release more IFN-
and TNF-
faster to influenza A virus infection than NK cells from KIR2DL3+/KIR2DL1+ and HLA-C2 homozygous subjects. Subanalysis revealed that the HLA-C-regulated, i.e. KIR2DL3+ NK cell subpopulation of HLA-C1 homozygous subjects responded more rapidly than their HLA-C-regulated, i.e. KIR2DL1+ counterpart in HLA-C2 homozygous subjects. This differential functional response was independent of Bw4/KIR3DL1 interactions. It was also not due to intrinsic difference between NK cell of HLA-C1 and HLA-C2 homozygous subjects, as demonstrated by equal cytotoxicity in the absence of HLA-C. In summary, these results provide first functional evidence for the epidemiological associations between specific KIR/HLA compound genotypes and protection against viral infection observed at the population level.
