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J Clin Invest. 2008 Mar;118(3):1017-26. doi: 10.1172/JCI32400.

Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses.

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Immunology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, Maryland 20892-1800, USA.


Genetic studies suggest a role for killer cell immunoglobulin-like receptor/HLA (KIR/HLA) compound genotypes in the outcome of viral infections, but functional data to explain these epidemiological observations have not been reported. Using an in vitro model of infection with influenza A virus (IAV), we attribute functional differences in human NK cell activity to distinct KIR/HLA genotypes. Multicolor flow cytometry revealed that the HLA-C-inhibited NK cell subset in HLA-C1 homozygous subjects was larger and responded more rapidly in IFN-gamma secretion and CD107a degranulation assays than its counterpart in HLA-C2 homozygous subjects. The differential IFN-gamma response was also observed at the level of bulk NK cells and was independent of KIR3DL1/HLA-Bw4 interactions. Moreover, the differential response was not caused by differences in NK cell maturation status and phenotype, nor by differences in the type I IFN response of IAV-infected accessory cells between HLA-C1 and HLA-C2 homozygous subjects. These results provide functional evidence for differential NK cell responsiveness depending on KIR/HLA genotype and may provide useful insights into differential innate immune responsiveness to viral infections such as IAV.

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