Cognate HLA absence in trans diminishes human NK cell education
Vanessa Landtwing, … , Obinna Chijioke, Christian Münz
Vanessa Landtwing, … , Obinna Chijioke, Christian Münz
Published August 29, 2016
Citation Information: J Clin Invest. 2016;126(10):3772-3782. https://doi.org/10.1172/JCI86923.
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Research Article Immunology

Cognate HLA absence in trans diminishes human NK cell education

Abstract

NK cells are innate lymphocytes with protective functions against viral infections and tumor formation. Human NK cells carry inhibitory killer cell Ig-like receptors (KIRs), which recognize distinct HLAs. NK cells with KIRs for self-HLA molecules acquire superior cytotoxicity against HLA– tumor cells during education for improved missing-self recognition. Here, we reconstituted mice with human hematopoietic cells from donors with homozygous KIR ligands or with a mix of hematopoietic cells from these homozygous donors, allowing assessment of the resulting KIR repertoire and NK cell education. We found that co-reconstitution with 2 KIR ligand–mismatched compartments did not alter the frequency of KIR-expressing NK cells. However, NK cell education was diminished in mice reconstituted with parallel HLA compartments due to a lack of cognate HLA molecules on leukocytes for the corresponding KIRs. This change in NK cell education in mixed human donor–reconstituted mice improved NK cell–mediated immune control of EBV infection, indicating that mixed hematopoietic cell populations could be exploited to improve NK cell reactivity against leukotropic pathogens. Taken together, these findings indicate that leukocytes lacking cognate HLA ligands can disarm KIR+ NK cells in a manner that may decrease HLA– tumor cell recognition but allows for improved NK cell–mediated immune control of a human γ-herpesvirus.

Authors

Vanessa Landtwing, Ana Raykova, Gaetana Pezzino, Vivien Béziat, Emanuela Marcenaro, Claudine Graf, Alessandro Moretta, Riccarda Capaul, Andrea Zbinden, Guido Ferlazzo, Karl-Johan Malmberg, Obinna Chijioke, Christian Münz

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Figure 3

Infection with EBV does not lead to skewing of KIR repertoire.

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Infection with EBV does not lead to skewing of KIR repertoire. HuNSG mic...
HuNSG mice were single reconstituted with donors homozygous for HLA-C and -B allotypes (HLA-C1, -C2, and -Bw4) or reconstituted with 2 donors disparate for allotype and HLA-A2 expression (mixed). Gray pie charts depict the frequencies of KIR+ and KIR– NK cells, and colored pie charts represent the indicated KIR+ NK cell subsets. (A–D) Subsets of KIR-expressing NK cells as a percentages of total KIR+ NK cells in spleens of EBV-infected huNSG mice. (E–P) Frequency of single KIR+ NK cells in spleens of huNSG mice at endpoint. Comparison of PBS controls with EBV-infected animals for frequency of KIR2DL1+, KIR2DL2/3+, or KIR3DL1+ NK cells in homozygous reconstituted mice with HLA-C1 donor (E–G), mixed reconstituted mice with cells derived from HLA-C1 (H–J) or -C2 (K–M) donors, and homozygous reconstituted mice with cells from HLA-C2 donors (M–P). Data are pooled from at least 3 independent experiments. n = 8–15 mice per group. Bars represent the mean (unpaired Student’s t test).