KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection

Nicole Caduff; Donal McHugh; Lisa Rieble; Catherine S. Forconi; John M. Ong'echa; Peter O. Oluoch; Ana Raykova; Anita Murer; Michelle Böni; Lara Zuppiger; Thomas F. Schulz; David J. Blackbourn; Obinna Chijioke; Ann M. Moormann; Christian Münz

doi:10.1016/j.celrep.2021.109056

KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection

Nicole Caduff, Donal McHugh, Lisa Rieble, Catherine S. Forconi, John M. Ong'echa, Peter O. Oluoch, Ana Raykova, Anita Murer, Michelle Böni, Lara Zuppiger, Thomas F. Schulz, David J. Blackbourn, Obinna Chijioke, Ann M. Moormann, Christian Münz^*

^*Corresponding author for this work

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

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Abstract

Herpesvirus infections shape the human natural killer (NK) cell compartment. While Epstein-Barr virus (EBV) expands immature NKG2A⁺ NK cells, human cytomegalovirus (CMV) drives accumulation of adaptive NKG2C⁺ NK cells. Kaposi sarcoma-associated herpesvirus (KSHV) is a close relative of EBV, and both are associated with lymphomas, including primary effusion lymphoma (PEL), which nearly always harbors both viruses. In this study, KSHV dual infection of mice with reconstituted human immune system components leads to the accumulation of CD56^–CD16⁺CD38⁺CXCR6⁺ NK cells. CD56^–CD16⁺ NK cells were also more frequently found in KSHV-seropositive Kenyan children. This NK cell subset is poorly cytotoxic against otherwise-NK-cell-susceptible and antibody-opsonized targets. Accordingly, NK cell depletion does not significantly alter KSHV infection in humanized mice. These data suggest that KSHV might escape NK-cell-mediated immune control by driving CD56^–CD16⁺ NK cell differentiation.

Original language	English
Article number	109056
Number of pages	20
Journal	Cell Reports
Volume	35
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2021.109056
Publication status	Published - 4 May 2021

Bibliographical note

Funding Information:
This research was supported in part by Cancer Research Switzerland , Switzerland ( KFS-4091-02-2017 ); KFSP-PrecisionMS and HMZ ImmunoTargET of the University of Zurich , Switzerland; the Cancer Research Center Zurich , Switzerland; the Vontobel Foundation , Switzerland; the Baugarten Foundation , Switzerland; the Sobek Foundation , Germany; the Swiss Vaccine Research Institute , Switzerland; Roche , Switzerland; Novartis , Switzerland; and the Swiss National Science Foundation , Switzerland ( 310030B_182827 and CRSII5_180323 ). A.M.M. was funded by a National Institutes of Health , United States, grant ( R01 CA189806 ). N.C. was supported by a career advancement grant from the University of Zurich , Switzerland ( FK-18-026 ). D.M. and M.B. were supported by MD-PhD fellowships from the Swiss National Science Foundation , Switzerland, and the Swiss Academy of Medical Sciences , Switzerland ( 323530_145247 and 323630_19938 ).

Keywords

CD56-negative NK cells
EBV
Epstein-Barr virus
humanized mouse model
Kaposi sarcoma-associated herpesvirus
KSHV
natural killer cells

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Caduff, N., McHugh, D., Rieble, L., Forconi, C. S., Ong'echa, J. M., Oluoch, P. O., Raykova, A., Murer, A., Böni, M., Zuppiger, L., Schulz, T. F., Blackbourn, D. J., Chijioke, O., Moormann, A. M., & Münz, C. (2021). KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection. Cell Reports, 35(5), Article 109056. https://doi.org/10.1016/j.celrep.2021.109056

Caduff, N, McHugh, D, Rieble, L, Forconi, CS, Ong'echa, JM, Oluoch, PO, Raykova, A, Murer, A, Böni, M, Zuppiger, L, Schulz, TF, Blackbourn, DJ, Chijioke, O, Moormann, AM & Münz, C 2021, 'KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection', Cell Reports, vol. 35, no. 5, 109056. https://doi.org/10.1016/j.celrep.2021.109056

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title = "KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection",

abstract = "Herpesvirus infections shape the human natural killer (NK) cell compartment. While Epstein-Barr virus (EBV) expands immature NKG2A+ NK cells, human cytomegalovirus (CMV) drives accumulation of adaptive NKG2C+ NK cells. Kaposi sarcoma-associated herpesvirus (KSHV) is a close relative of EBV, and both are associated with lymphomas, including primary effusion lymphoma (PEL), which nearly always harbors both viruses. In this study, KSHV dual infection of mice with reconstituted human immune system components leads to the accumulation of CD56–CD16+CD38+CXCR6+ NK cells. CD56–CD16+ NK cells were also more frequently found in KSHV-seropositive Kenyan children. This NK cell subset is poorly cytotoxic against otherwise-NK-cell-susceptible and antibody-opsonized targets. Accordingly, NK cell depletion does not significantly alter KSHV infection in humanized mice. These data suggest that KSHV might escape NK-cell-mediated immune control by driving CD56–CD16+ NK cell differentiation.",

keywords = "CD56-negative NK cells, EBV, Epstein-Barr virus, humanized mouse model, Kaposi sarcoma-associated herpesvirus, KSHV, natural killer cells",

author = "Nicole Caduff and Donal McHugh and Lisa Rieble and Forconi, {Catherine S.} and Ong'echa, {John M.} and Oluoch, {Peter O.} and Ana Raykova and Anita Murer and Michelle B{\"o}ni and Lara Zuppiger and Schulz, {Thomas F.} and Blackbourn, {David J.} and Obinna Chijioke and Moormann, {Ann M.} and Christian M{\"u}nz",

note = "Funding Information: This research was supported in part by Cancer Research Switzerland , Switzerland ( KFS-4091-02-2017 ); KFSP-PrecisionMS and HMZ ImmunoTargET of the University of Zurich , Switzerland; the Cancer Research Center Zurich , Switzerland; the Vontobel Foundation , Switzerland; the Baugarten Foundation , Switzerland; the Sobek Foundation , Germany; the Swiss Vaccine Research Institute , Switzerland; Roche , Switzerland; Novartis , Switzerland; and the Swiss National Science Foundation , Switzerland ( 310030B_182827 and CRSII5_180323 ). A.M.M. was funded by a National Institutes of Health , United States, grant ( R01 CA189806 ). N.C. was supported by a career advancement grant from the University of Zurich , Switzerland ( FK-18-026 ). D.M. and M.B. were supported by MD-PhD fellowships from the Swiss National Science Foundation , Switzerland, and the Swiss Academy of Medical Sciences , Switzerland ( 323530_145247 and 323630_19938 ). ",

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doi = "10.1016/j.celrep.2021.109056",

language = "English",

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journal = "Cell Reports",

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T1 - KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection

AU - Caduff, Nicole

AU - McHugh, Donal

AU - Rieble, Lisa

AU - Forconi, Catherine S.

AU - Ong'echa, John M.

AU - Oluoch, Peter O.

AU - Raykova, Ana

AU - Murer, Anita

AU - Böni, Michelle

AU - Zuppiger, Lara

AU - Schulz, Thomas F.

AU - Blackbourn, David J.

AU - Chijioke, Obinna

AU - Moormann, Ann M.

AU - Münz, Christian

N1 - Funding Information: This research was supported in part by Cancer Research Switzerland , Switzerland ( KFS-4091-02-2017 ); KFSP-PrecisionMS and HMZ ImmunoTargET of the University of Zurich , Switzerland; the Cancer Research Center Zurich , Switzerland; the Vontobel Foundation , Switzerland; the Baugarten Foundation , Switzerland; the Sobek Foundation , Germany; the Swiss Vaccine Research Institute , Switzerland; Roche , Switzerland; Novartis , Switzerland; and the Swiss National Science Foundation , Switzerland ( 310030B_182827 and CRSII5_180323 ). A.M.M. was funded by a National Institutes of Health , United States, grant ( R01 CA189806 ). N.C. was supported by a career advancement grant from the University of Zurich , Switzerland ( FK-18-026 ). D.M. and M.B. were supported by MD-PhD fellowships from the Swiss National Science Foundation , Switzerland, and the Swiss Academy of Medical Sciences , Switzerland ( 323530_145247 and 323630_19938 ).

PY - 2021/5/4

Y1 - 2021/5/4

N2 - Herpesvirus infections shape the human natural killer (NK) cell compartment. While Epstein-Barr virus (EBV) expands immature NKG2A+ NK cells, human cytomegalovirus (CMV) drives accumulation of adaptive NKG2C+ NK cells. Kaposi sarcoma-associated herpesvirus (KSHV) is a close relative of EBV, and both are associated with lymphomas, including primary effusion lymphoma (PEL), which nearly always harbors both viruses. In this study, KSHV dual infection of mice with reconstituted human immune system components leads to the accumulation of CD56–CD16+CD38+CXCR6+ NK cells. CD56–CD16+ NK cells were also more frequently found in KSHV-seropositive Kenyan children. This NK cell subset is poorly cytotoxic against otherwise-NK-cell-susceptible and antibody-opsonized targets. Accordingly, NK cell depletion does not significantly alter KSHV infection in humanized mice. These data suggest that KSHV might escape NK-cell-mediated immune control by driving CD56–CD16+ NK cell differentiation.

AB - Herpesvirus infections shape the human natural killer (NK) cell compartment. While Epstein-Barr virus (EBV) expands immature NKG2A+ NK cells, human cytomegalovirus (CMV) drives accumulation of adaptive NKG2C+ NK cells. Kaposi sarcoma-associated herpesvirus (KSHV) is a close relative of EBV, and both are associated with lymphomas, including primary effusion lymphoma (PEL), which nearly always harbors both viruses. In this study, KSHV dual infection of mice with reconstituted human immune system components leads to the accumulation of CD56–CD16+CD38+CXCR6+ NK cells. CD56–CD16+ NK cells were also more frequently found in KSHV-seropositive Kenyan children. This NK cell subset is poorly cytotoxic against otherwise-NK-cell-susceptible and antibody-opsonized targets. Accordingly, NK cell depletion does not significantly alter KSHV infection in humanized mice. These data suggest that KSHV might escape NK-cell-mediated immune control by driving CD56–CD16+ NK cell differentiation.

KW - CD56-negative NK cells

KW - EBV

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KW - humanized mouse model

KW - Kaposi sarcoma-associated herpesvirus

KW - KSHV

KW - natural killer cells

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DO - 10.1016/j.celrep.2021.109056

M3 - Article

C2 - 33951431

AN - SCOPUS:85105035012

SN - 2211-1247

VL - 35

JO - Cell Reports

JF - Cell Reports

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ER -

KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection

Abstract

Bibliographical note

Keywords

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