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

Autor:	Philippon C; Precision Immunotherapy Alliance (PRIMA), Institute for Clinical medicine, The University of Oslo, Oslo, Norway., Tao S; Department of Biomedical Informatics, and Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.; Blood Center of Zhejiang Province, Key Laboratory of Blood Safety Research of Zhejiang Province, Hangzhou, Zhejiang, China., Clement D; Precision Immunotherapy Alliance (PRIMA), Institute for Clinical medicine, The University of Oslo, Oslo, Norway., Haroun-Izquierdo A; Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden., Kichula KM; Department of Biomedical Informatics, and Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO., Netskar H; Precision Immunotherapy Alliance (PRIMA), Institute for Clinical medicine, The University of Oslo, Oslo, Norway., Brandt L; Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden., Oei VS; Precision Immunotherapy Alliance (PRIMA), Institute for Clinical medicine, The University of Oslo, Oslo, Norway., Kanaya M; Precision Immunotherapy Alliance (PRIMA), Institute for Clinical medicine, The University of Oslo, Oslo, Norway., Lanuza PM; Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden., Schaffer M; Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden., Goodridge JP; Fate Therapeutics Inc, San Diego, CA., Horowitz A; Department of Oncological Sciences, The Marc and Jennifer Lipshultz Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY., Zhu F; Blood Center of Zhejiang Province, Key Laboratory of Blood Safety Research of Zhejiang Province, Hangzhou, Zhejiang, China., Hammer Q; Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden., Sohlberg E; Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden., Majhi RK; Precision Immunotherapy Alliance (PRIMA), Institute for Clinical medicine, The University of Oslo, Oslo, Norway., Kveberg L; Precision Immunotherapy Alliance (PRIMA), Institute for Clinical medicine, The University of Oslo, Oslo, Norway.; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Önfelt B; Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden., Norman PJ; Department of Biomedical Informatics, and Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO., Malmberg KJ; Precision Immunotherapy Alliance (PRIMA), Institute for Clinical medicine, The University of Oslo, Oslo, Norway.; Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden.; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2023 Aug 22; Vol. 7 (16), pp. 4492-4504.
DOI:	10.1182/bloodadvances.2023009827
Abstrakt:	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. (© 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.)
Databáze:	MEDLINE
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