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Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires

The functionality of natural killer (NK) cells is tuned during education and is associated with remodeling of the lysosomal compartment. We hypothesized that genetic variation in killer cell immunoglobulin-like receptor (KIR) and HLA, which is known to influence the functional strength of NK cells,...

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Autores principales: Philippon, Camille, Tao, Sudan, Clement, Dennis, Haroun-Izquierdo, Alvaro, Kichula, Katherine M., Netskar, Herman, Brandt, Ludwig, Oei, Vincent Sheng, Kanaya, Minoru, Lanuza, Pilar Maria, Schaffer, Marie, Goodridge, Jodie P., Horowitz, Amir, Zhu, Faming, Hammer, Quirin, Sohlberg, Ebba, Majhi, Rakesh Kumar, Kveberg, Lise, Önfelt, Björn, Norman, Paul J., Malmberg, Karl-Johan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440473/
https://www.ncbi.nlm.nih.gov/pubmed/37327114
http://dx.doi.org/10.1182/bloodadvances.2023009827
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author Philippon, Camille
Tao, Sudan
Clement, Dennis
Haroun-Izquierdo, Alvaro
Kichula, Katherine M.
Netskar, Herman
Brandt, Ludwig
Oei, Vincent Sheng
Kanaya, Minoru
Lanuza, Pilar Maria
Schaffer, Marie
Goodridge, Jodie P.
Horowitz, Amir
Zhu, Faming
Hammer, Quirin
Sohlberg, Ebba
Majhi, Rakesh Kumar
Kveberg, Lise
Önfelt, Björn
Norman, Paul J.
Malmberg, Karl-Johan
author_facet Philippon, Camille
Tao, Sudan
Clement, Dennis
Haroun-Izquierdo, Alvaro
Kichula, Katherine M.
Netskar, Herman
Brandt, Ludwig
Oei, Vincent Sheng
Kanaya, Minoru
Lanuza, Pilar Maria
Schaffer, Marie
Goodridge, Jodie P.
Horowitz, Amir
Zhu, Faming
Hammer, Quirin
Sohlberg, Ebba
Majhi, Rakesh Kumar
Kveberg, Lise
Önfelt, Björn
Norman, Paul J.
Malmberg, Karl-Johan
author_sort Philippon, Camille
collection PubMed
description The functionality of natural killer (NK) cells is tuned during education and is associated with remodeling of the lysosomal compartment. We hypothesized that genetic variation in killer cell immunoglobulin-like receptor (KIR) and HLA, which is known to influence the functional strength of NK cells, fine-tunes the payload of effector molecules stored in secretory lysosomes. To address this possibility, we performed a high-resolution analysis of KIR and HLA class I genes in 365 blood donors and linked genotypes to granzyme B loading and functional phenotypes. We found that granzyme B levels varied across individuals but were stable over time in each individual and genetically determined by allelic variation in HLA class I genes. A broad mapping of surface receptors and lysosomal effector molecules revealed that DNAM-1 and granzyme B levels served as robust metric of the functional state in NK cells. Variation in granzyme B levels at rest was tightly linked to the lytic hit and downstream killing of major histocompatibility complex–deficient target cells. Together, these data provide insights into how variation in genetically hardwired receptor pairs tunes the releasable granzyme B pool in NK cells, resulting in predictable hierarchies in global NK cell function.
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spelling pubmed-104404732023-08-22 Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires Philippon, Camille Tao, Sudan Clement, Dennis Haroun-Izquierdo, Alvaro Kichula, Katherine M. Netskar, Herman Brandt, Ludwig Oei, Vincent Sheng Kanaya, Minoru Lanuza, Pilar Maria Schaffer, Marie Goodridge, Jodie P. Horowitz, Amir Zhu, Faming Hammer, Quirin Sohlberg, Ebba Majhi, Rakesh Kumar Kveberg, Lise Önfelt, Björn Norman, Paul J. Malmberg, Karl-Johan Blood Adv Immunobiology and Immunotherapy The functionality of natural killer (NK) cells is tuned during education and is associated with remodeling of the lysosomal compartment. We hypothesized that genetic variation in killer cell immunoglobulin-like receptor (KIR) and HLA, which is known to influence the functional strength of NK cells, fine-tunes the payload of effector molecules stored in secretory lysosomes. To address this possibility, we performed a high-resolution analysis of KIR and HLA class I genes in 365 blood donors and linked genotypes to granzyme B loading and functional phenotypes. We found that granzyme B levels varied across individuals but were stable over time in each individual and genetically determined by allelic variation in HLA class I genes. A broad mapping of surface receptors and lysosomal effector molecules revealed that DNAM-1 and granzyme B levels served as robust metric of the functional state in NK cells. Variation in granzyme B levels at rest was tightly linked to the lytic hit and downstream killing of major histocompatibility complex–deficient target cells. Together, these data provide insights into how variation in genetically hardwired receptor pairs tunes the releasable granzyme B pool in NK cells, resulting in predictable hierarchies in global NK cell function. The American Society of Hematology 2023-06-20 /pmc/articles/PMC10440473/ /pubmed/37327114 http://dx.doi.org/10.1182/bloodadvances.2023009827 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Immunobiology and Immunotherapy
Philippon, Camille
Tao, Sudan
Clement, Dennis
Haroun-Izquierdo, Alvaro
Kichula, Katherine M.
Netskar, Herman
Brandt, Ludwig
Oei, Vincent Sheng
Kanaya, Minoru
Lanuza, Pilar Maria
Schaffer, Marie
Goodridge, Jodie P.
Horowitz, Amir
Zhu, Faming
Hammer, Quirin
Sohlberg, Ebba
Majhi, Rakesh Kumar
Kveberg, Lise
Önfelt, Björn
Norman, Paul J.
Malmberg, Karl-Johan
Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires
title Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires
title_full Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires
title_fullStr Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires
title_full_unstemmed Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires
title_short Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires
title_sort allelic variation of kir and hla tunes the cytolytic payload and determines functional hierarchy of nk cell repertoires
topic Immunobiology and Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440473/
https://www.ncbi.nlm.nih.gov/pubmed/37327114
http://dx.doi.org/10.1182/bloodadvances.2023009827
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