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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

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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 1

Mixed reconstitution of human immune system compartments from HLA-mismatched HPCs in NSG mice.

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Mixed reconstitution of human immune system compartments from HLA-mismat...
(A) Representative experimental overview. Three types of experimental groups were used: two groups reconstituted homozygously for HLA-C and -B allotypes (HLA-C1, -C2, and -Bw4), while disparate for HLA-A2, and the third group with a mix of both. (B) Reconstitution of human immune cell compartments in the 3 experimental groups as a percentage of human CD45+ lymphocytes. (C) Ratio of HLA-C1 donor versus HLA-C2 donor frequencies as distinguished by HLA-A2 expression in immune cell compartments of mixed reconstituted huNSG mice. Data were pooled from at least 4 independent experiments. n = 34–49. Bars represent the mean in the respective graphs.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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