Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies

Moriya Gamliel; Debra Goldman-Wohl; Batya Isaacson; Chamutal Gur; Natan Stein; Rachel Yamin; Michael Berger; Myriam Grunewald; Eli Keshet; Yoach Rais; Chamutal Bornstein; Eyal David; Adam Jelinski; Iris Eisenberg; Caryn Greenfield; Arbel Ben-David; Tal Imbar; Ronit Gilad; Ronit Haimov-Kochman; David Mankuta; Matan Elami-Suzin; Ido Amit; Jacob H. Hanna; Simcha Yagel; Ofer Mandelboim

doi:10.1016/j.immuni.2018.03.030

Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies

Moriya Gamliel, Debra Goldman-Wohl, Batya Isaacson, Chamutal Gur, Natan Stein, Rachel Yamin, Michael Berger, Myriam Grunewald, Eli Keshet, Yoach Rais, Chamutal Bornstein, Eyal David, Adam Jelinski, Iris Eisenberg, Caryn Greenfield, Arbel Ben-David, Tal Imbar, Ronit Gilad, Ronit Haimov-Kochman, David MankutaMatan Elami-Suzin, Ido Amit, Jacob H. Hanna, Simcha Yagel, Ofer Mandelboim^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

192 Scopus citations

Abstract

Natural killer cells (NKs) are abundant in the human decidua, regulating trophoblast invasion and angiogenesis. Several diseases of poor placental development are associated with first pregnancies, so we thus looked to characterize differences in decidual NKs (dNKs) in first versus repeated pregnancies. We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature, and is characterized by high expression of the receptors NKG2C and LILRB1. We named these cells Pregnancy Trained decidual NK cells (PTdNKs). PTdNKs have open chromatin around the enhancers of IFNG and VEGFA. Activation of PTdNKs led to increased production and secretion of IFN-γ and VEGFα with the latter supporting vascular sprouting and tumor growth. The precursors of PTdNKs seem to be found in the endometrium. Because repeated pregnancies are associated with improved placentation, we propose that PTdNKs, which are present primarily in repeated pregnancies, might be involved in proper placentation. Natural killer cells are present in the human decidua, regulating trophoblast invasion and angiogenesis. Here, Gamliel et al. report on a special subset of human decidual natural killer cells, which “remember” pregnancy and better support subsequent pregnancies. This might explain why first pregnancies are at increased risk of developing diseases of poor placentation.

Original language	American English
Pages (from-to)	951-962.e5
Journal	Immunity
Volume	48
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2018.03.030
State	Published - 15 May 2018

Bibliographical note

Funding Information:
This work was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement number 320473-BacNK. Further support came from the Israel Science Foundation, the GIF foundation, the Lewis family foundation, the ICRF professorship grant, the Helmholtz Israel grant and the Rosetrees Trust (all to O.M.). J.H.H. is supported by European Research Council, Flight Attendant Medical Research Council (FAMRI), Israel Science Foundation (ISF-ICORE, ISF-NFSC, ISF-Regular & ISF-Morasha programs), ICRF, and HFSP & New York Stem Cell Foundation (NYSCF). J.H.H. is a New York Stem Cell Foundation (NYSCF)–Robertson Investigator. We wish to thank the Bioinformatics Unit of the I-CORE Computation Center at the Hebrew University and Hadassah for the transcriptome analysis and Dr. Shari Orlanski for analyzing part of the epigenetic data. O.M. is a Crown Professor of Molecular Immunology. M. Gamliel is supported by the Hoffman Leadership and Responsibility fund, at the Hebrew University.

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

LILRB1
NKG2C
decidua
gravidity
great obstetrical disorders
natural killer cells
pregnancy
trained immunity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2018.03.030

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Gamliel, M., Goldman-Wohl, D., Isaacson, B., Gur, C., Stein, N., Yamin, R., Berger, M., Grunewald, M., Keshet, E., Rais, Y., Bornstein, C., David, E., Jelinski, A., Eisenberg, I., Greenfield, C., Ben-David, A., Imbar, T., Gilad, R., Haimov-Kochman, R., ... Mandelboim, O. (2018). Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies. Immunity, 48(5), 951-962.e5. https://doi.org/10.1016/j.immuni.2018.03.030

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title = "Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies",

abstract = "Natural killer cells (NKs) are abundant in the human decidua, regulating trophoblast invasion and angiogenesis. Several diseases of poor placental development are associated with first pregnancies, so we thus looked to characterize differences in decidual NKs (dNKs) in first versus repeated pregnancies. We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature, and is characterized by high expression of the receptors NKG2C and LILRB1. We named these cells Pregnancy Trained decidual NK cells (PTdNKs). PTdNKs have open chromatin around the enhancers of IFNG and VEGFA. Activation of PTdNKs led to increased production and secretion of IFN-γ and VEGFα with the latter supporting vascular sprouting and tumor growth. The precursors of PTdNKs seem to be found in the endometrium. Because repeated pregnancies are associated with improved placentation, we propose that PTdNKs, which are present primarily in repeated pregnancies, might be involved in proper placentation. Natural killer cells are present in the human decidua, regulating trophoblast invasion and angiogenesis. Here, Gamliel et al. report on a special subset of human decidual natural killer cells, which “remember” pregnancy and better support subsequent pregnancies. This might explain why first pregnancies are at increased risk of developing diseases of poor placentation.",

keywords = "LILRB1, NKG2C, decidua, gravidity, great obstetrical disorders, natural killer cells, pregnancy, trained immunity",

author = "Moriya Gamliel and Debra Goldman-Wohl and Batya Isaacson and Chamutal Gur and Natan Stein and Rachel Yamin and Michael Berger and Myriam Grunewald and Eli Keshet and Yoach Rais and Chamutal Bornstein and Eyal David and Adam Jelinski and Iris Eisenberg and Caryn Greenfield and Arbel Ben-David and Tal Imbar and Ronit Gilad and Ronit Haimov-Kochman and David Mankuta and Matan Elami-Suzin and Ido Amit and Hanna, {Jacob H.} and Simcha Yagel and Ofer Mandelboim",

note = "Funding Information: This work was supported by the European Research Council under the European Union{\textquoteright}s Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement number 320473-BacNK. Further support came from the Israel Science Foundation, the GIF foundation, the Lewis family foundation, the ICRF professorship grant, the Helmholtz Israel grant and the Rosetrees Trust (all to O.M.). J.H.H. is supported by European Research Council, Flight Attendant Medical Research Council (FAMRI), Israel Science Foundation (ISF-ICORE, ISF-NFSC, ISF-Regular & ISF-Morasha programs), ICRF, and HFSP & New York Stem Cell Foundation (NYSCF). J.H.H. is a New York Stem Cell Foundation (NYSCF)–Robertson Investigator. We wish to thank the Bioinformatics Unit of the I-CORE Computation Center at the Hebrew University and Hadassah for the transcriptome analysis and Dr. Shari Orlanski for analyzing part of the epigenetic data. O.M. is a Crown Professor of Molecular Immunology. M. Gamliel is supported by the Hoffman Leadership and Responsibility fund, at the Hebrew University. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = may,

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doi = "10.1016/j.immuni.2018.03.030",

language = "American English",

volume = "48",

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Gamliel, M, Goldman-Wohl, D, Isaacson, B, Gur, C, Stein, N, Yamin, R, Berger, M , Grunewald, M, Keshet, E, Rais, Y, Bornstein, C, David, E, Jelinski, A, Eisenberg, I, Greenfield, C, Ben-David, A, Imbar, T, Gilad, R, Haimov-Kochman, R, Mankuta, D, Elami-Suzin, M, Amit, I, Hanna, JH, Yagel, S & Mandelboim, O 2018, 'Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies', Immunity, vol. 48, no. 5, pp. 951-962.e5. https://doi.org/10.1016/j.immuni.2018.03.030

TY - JOUR

T1 - Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies

AU - Gamliel, Moriya

AU - Goldman-Wohl, Debra

AU - Isaacson, Batya

AU - Gur, Chamutal

AU - Stein, Natan

AU - Yamin, Rachel

AU - Berger, Michael

AU - Grunewald, Myriam

AU - Keshet, Eli

AU - Rais, Yoach

AU - Bornstein, Chamutal

AU - David, Eyal

AU - Jelinski, Adam

AU - Eisenberg, Iris

AU - Greenfield, Caryn

AU - Ben-David, Arbel

AU - Imbar, Tal

AU - Gilad, Ronit

AU - Haimov-Kochman, Ronit

AU - Mankuta, David

AU - Elami-Suzin, Matan

AU - Amit, Ido

AU - Hanna, Jacob H.

AU - Yagel, Simcha

AU - Mandelboim, Ofer

N1 - Funding Information: This work was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement number 320473-BacNK. Further support came from the Israel Science Foundation, the GIF foundation, the Lewis family foundation, the ICRF professorship grant, the Helmholtz Israel grant and the Rosetrees Trust (all to O.M.). J.H.H. is supported by European Research Council, Flight Attendant Medical Research Council (FAMRI), Israel Science Foundation (ISF-ICORE, ISF-NFSC, ISF-Regular & ISF-Morasha programs), ICRF, and HFSP & New York Stem Cell Foundation (NYSCF). J.H.H. is a New York Stem Cell Foundation (NYSCF)–Robertson Investigator. We wish to thank the Bioinformatics Unit of the I-CORE Computation Center at the Hebrew University and Hadassah for the transcriptome analysis and Dr. Shari Orlanski for analyzing part of the epigenetic data. O.M. is a Crown Professor of Molecular Immunology. M. Gamliel is supported by the Hoffman Leadership and Responsibility fund, at the Hebrew University. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/5/15

Y1 - 2018/5/15

N2 - Natural killer cells (NKs) are abundant in the human decidua, regulating trophoblast invasion and angiogenesis. Several diseases of poor placental development are associated with first pregnancies, so we thus looked to characterize differences in decidual NKs (dNKs) in first versus repeated pregnancies. We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature, and is characterized by high expression of the receptors NKG2C and LILRB1. We named these cells Pregnancy Trained decidual NK cells (PTdNKs). PTdNKs have open chromatin around the enhancers of IFNG and VEGFA. Activation of PTdNKs led to increased production and secretion of IFN-γ and VEGFα with the latter supporting vascular sprouting and tumor growth. The precursors of PTdNKs seem to be found in the endometrium. Because repeated pregnancies are associated with improved placentation, we propose that PTdNKs, which are present primarily in repeated pregnancies, might be involved in proper placentation. Natural killer cells are present in the human decidua, regulating trophoblast invasion and angiogenesis. Here, Gamliel et al. report on a special subset of human decidual natural killer cells, which “remember” pregnancy and better support subsequent pregnancies. This might explain why first pregnancies are at increased risk of developing diseases of poor placentation.

AB - Natural killer cells (NKs) are abundant in the human decidua, regulating trophoblast invasion and angiogenesis. Several diseases of poor placental development are associated with first pregnancies, so we thus looked to characterize differences in decidual NKs (dNKs) in first versus repeated pregnancies. We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature, and is characterized by high expression of the receptors NKG2C and LILRB1. We named these cells Pregnancy Trained decidual NK cells (PTdNKs). PTdNKs have open chromatin around the enhancers of IFNG and VEGFA. Activation of PTdNKs led to increased production and secretion of IFN-γ and VEGFα with the latter supporting vascular sprouting and tumor growth. The precursors of PTdNKs seem to be found in the endometrium. Because repeated pregnancies are associated with improved placentation, we propose that PTdNKs, which are present primarily in repeated pregnancies, might be involved in proper placentation. Natural killer cells are present in the human decidua, regulating trophoblast invasion and angiogenesis. Here, Gamliel et al. report on a special subset of human decidual natural killer cells, which “remember” pregnancy and better support subsequent pregnancies. This might explain why first pregnancies are at increased risk of developing diseases of poor placentation.

KW - LILRB1

KW - NKG2C

KW - decidua

KW - gravidity

KW - great obstetrical disorders

KW - natural killer cells

KW - pregnancy

KW - trained immunity

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U2 - 10.1016/j.immuni.2018.03.030

DO - 10.1016/j.immuni.2018.03.030

M3 - Article

C2 - 29768178

AN - SCOPUS:85046652866

SN - 1074-7613

VL - 48

SP - 951-962.e5

JO - Immunity

JF - Immunity

IS - 5

ER -

Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies

Abstract

Bibliographical note

Keywords

UN SDGs

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