Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses
Golo Ahlenstiel, Maureen P. Martin, Xiaojiang Gao, Mary Carrington, Barbara Rehermann
Golo Ahlenstiel, Maureen P. Martin, Xiaojiang Gao, Mary Carrington, Barbara Rehermann
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Research Article Virology

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

Abstract

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-γ secretion and CD107a degranulation assays than its counterpart in HLA-C2 homozygous subjects. The differential IFN-γ 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.

Authors

Golo Ahlenstiel, Maureen P. Martin, Xiaojiang Gao, Mary Carrington, Barbara Rehermann

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Figure 1

Identification and quantitation of HLA-C–inhibited NK cells by flow cytometry.

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Identification and quantitation of HLA-C–inhibited NK cells by flow cyto...
(A) Gating strategy used to identify HLA-C–inhibited NK cells by flow cytometry. After gating on single cells (forward scatter–height versus forward scatter–area) and lymphocytes (forward scatter versus side scatter), NK cells were identified by gating on CD56+ cells and by excluding CD3+ T cells, CD14+ monocytes, CD19+ B cells, and EMA+ dead cells. Samples from HLA-C1/C1 subjects were stained with antibodies to KIR2DL3, and samples from HLA-C2/C2 subjects were stained with antibodies to KIR2DL1. All samples were stained with antibodies to KIR3DL1 to allow further subset analysis as shown in Figure 5. Numbers indicate the percentage of events in each quadrant. (B) Frequency of HLA-C–inhibited NK cells in PBMCs. The HLA-C–inhibited NK cell subset consists of KIR2DL3+ NK cells in HLA-C1 homozygous subjects and KIR2DL1+ NK cells in HLA-C2 homozygous subjects. Horizontal lines indicate the mean.