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CXCR6(+) NK Cells in Human Fetal Liver and Spleen Possess Unique Phenotypic and Functional Capabilities

Tissue-resident Natural Killer (NK) cells vary in phenotype according to tissue origin, but are typically CD56(bright), CXCR6(+), and CD69(+). NK cells appear very early in fetal development, but little is known about when markers of tissue residency appear during gestation and whether the expressio...

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Autores principales: Angelo, Laura S., Bimler, Lynn H., Nikzad, Rana, Aviles-Padilla, Kevin, Paust, Silke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433986/
https://www.ncbi.nlm.nih.gov/pubmed/30941128
http://dx.doi.org/10.3389/fimmu.2019.00469
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author Angelo, Laura S.
Bimler, Lynn H.
Nikzad, Rana
Aviles-Padilla, Kevin
Paust, Silke
author_facet Angelo, Laura S.
Bimler, Lynn H.
Nikzad, Rana
Aviles-Padilla, Kevin
Paust, Silke
author_sort Angelo, Laura S.
collection PubMed
description Tissue-resident Natural Killer (NK) cells vary in phenotype according to tissue origin, but are typically CD56(bright), CXCR6(+), and CD69(+). NK cells appear very early in fetal development, but little is known about when markers of tissue residency appear during gestation and whether the expression of these markers, most notably the chemokine receptor CXCR6, are associated with differences in functional capability. Using multi-parametric flow cytometry, we interrogated fetal liver and spleen NK cells for the expression of a multitude of extracellular markers associated with NK cell maturation, differentiation, and migration. We analyzed total NK cells from fetal liver and spleen and compared them to their adult liver and spleen counterparts, and peripheral blood (PB) NK. We found that fetal NK cells resemble each other and their adult counterparts more than PB NK. Maturity markers including CD16, CD57, and KIR are lower in fetal NK cells than PB, and markers associated with an immature phenotype are higher in fetal liver and spleen NK cells (NKG2A, CD94, and CD27). However, T-bet/EOMES transcription factor profiles are similar amongst fetal and adult liver and spleen NK cells (T-bet(−)/EOMES(+)) but differ from PB NK cells (T-bet(+)EOMES(−)). Further, donor-matched fetal liver and spleen NK cells share similar patterns of expression for most markers as a function of gestational age. We also performed functional studies including degranulation, cytotoxicity, and antibody-dependent cellular cytotoxicity (ADCC) assays. Fetal liver and spleen NK cells displayed limited cytotoxic effector function in chromium release assays but produced copious amounts of TNFα and IFNγ, and degranulated efficiently in response to stimulation with PMA/ionomycin. Further, CXCR6(+) NK cells in fetal liver and spleen produce more cytokines and degranulate more robustly than their CXCR6(−) counterparts, even though CXCR6(+) NK cells in fetal liver and spleen possess an immature phenotype. Major differences between CXCR6(−) and + NK cell subsets appear to occur later in development, as a distinct CXCR6(+) NK cell phenotype is much more clearly defined in PB. In conclusion, fetal liver and spleen NK cells share similar phenotypes, resemble their adult counterparts, and already possess a distinct CXCR6(+) NK cell population with discrete functional capabilities.
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spelling pubmed-64339862019-04-02 CXCR6(+) NK Cells in Human Fetal Liver and Spleen Possess Unique Phenotypic and Functional Capabilities Angelo, Laura S. Bimler, Lynn H. Nikzad, Rana Aviles-Padilla, Kevin Paust, Silke Front Immunol Immunology Tissue-resident Natural Killer (NK) cells vary in phenotype according to tissue origin, but are typically CD56(bright), CXCR6(+), and CD69(+). NK cells appear very early in fetal development, but little is known about when markers of tissue residency appear during gestation and whether the expression of these markers, most notably the chemokine receptor CXCR6, are associated with differences in functional capability. Using multi-parametric flow cytometry, we interrogated fetal liver and spleen NK cells for the expression of a multitude of extracellular markers associated with NK cell maturation, differentiation, and migration. We analyzed total NK cells from fetal liver and spleen and compared them to their adult liver and spleen counterparts, and peripheral blood (PB) NK. We found that fetal NK cells resemble each other and their adult counterparts more than PB NK. Maturity markers including CD16, CD57, and KIR are lower in fetal NK cells than PB, and markers associated with an immature phenotype are higher in fetal liver and spleen NK cells (NKG2A, CD94, and CD27). However, T-bet/EOMES transcription factor profiles are similar amongst fetal and adult liver and spleen NK cells (T-bet(−)/EOMES(+)) but differ from PB NK cells (T-bet(+)EOMES(−)). Further, donor-matched fetal liver and spleen NK cells share similar patterns of expression for most markers as a function of gestational age. We also performed functional studies including degranulation, cytotoxicity, and antibody-dependent cellular cytotoxicity (ADCC) assays. Fetal liver and spleen NK cells displayed limited cytotoxic effector function in chromium release assays but produced copious amounts of TNFα and IFNγ, and degranulated efficiently in response to stimulation with PMA/ionomycin. Further, CXCR6(+) NK cells in fetal liver and spleen produce more cytokines and degranulate more robustly than their CXCR6(−) counterparts, even though CXCR6(+) NK cells in fetal liver and spleen possess an immature phenotype. Major differences between CXCR6(−) and + NK cell subsets appear to occur later in development, as a distinct CXCR6(+) NK cell phenotype is much more clearly defined in PB. In conclusion, fetal liver and spleen NK cells share similar phenotypes, resemble their adult counterparts, and already possess a distinct CXCR6(+) NK cell population with discrete functional capabilities. Frontiers Media S.A. 2019-03-19 /pmc/articles/PMC6433986/ /pubmed/30941128 http://dx.doi.org/10.3389/fimmu.2019.00469 Text en Copyright © 2019 Angelo, Bimler, Nikzad, Aviles-Padilla and Paust. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Angelo, Laura S.
Bimler, Lynn H.
Nikzad, Rana
Aviles-Padilla, Kevin
Paust, Silke
CXCR6(+) NK Cells in Human Fetal Liver and Spleen Possess Unique Phenotypic and Functional Capabilities
title CXCR6(+) NK Cells in Human Fetal Liver and Spleen Possess Unique Phenotypic and Functional Capabilities
title_full CXCR6(+) NK Cells in Human Fetal Liver and Spleen Possess Unique Phenotypic and Functional Capabilities
title_fullStr CXCR6(+) NK Cells in Human Fetal Liver and Spleen Possess Unique Phenotypic and Functional Capabilities
title_full_unstemmed CXCR6(+) NK Cells in Human Fetal Liver and Spleen Possess Unique Phenotypic and Functional Capabilities
title_short CXCR6(+) NK Cells in Human Fetal Liver and Spleen Possess Unique Phenotypic and Functional Capabilities
title_sort cxcr6(+) nk cells in human fetal liver and spleen possess unique phenotypic and functional capabilities
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433986/
https://www.ncbi.nlm.nih.gov/pubmed/30941128
http://dx.doi.org/10.3389/fimmu.2019.00469
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