KIR3DS1 directs NK cell-mediated protection against human adenovirus infections

Johannes M Jung; Wilhelm Ching; Martin E Baumdick; Helga Hofmann-Sieber; Jens B Bosse; Tobias Koyro; Kimberly J Möller; Lucy Wegner; Annika Niehrs; Kristina Russu; Mareike Ohms; Wenli Zhang; Anja Ehrhardt; Kevin Duisters; Eric Spierings; Angelique Hölzemer; Christian Körner; Suze A Jansen; Sven Peine; Ingo Königs; Marc Lütgehetmann; Daniel Perez; Konrad Reinshagen; Caroline A Lindemans; Marcus Altfeld; Mirjam Belderbos; Thomas Dobner; Madeleine J Bunders

doi:10.1126/sciimmunol.abe2942

KIR3DS1 directs NK cell-mediated protection against human adenovirus infections

Johannes M Jung, Wilhelm Ching, Martin E Baumdick, Helga Hofmann-Sieber, Jens B Bosse, Tobias Koyro, Kimberly J Möller, Lucy Wegner, Annika Niehrs, Kristina Russu, Mareike Ohms, Wenli Zhang, Anja Ehrhardt, Kevin Duisters, Eric Spierings, Angelique Hölzemer, Christian Körner, Suze A Jansen, Sven Peine, Ingo KönigsMarc Lütgehetmann, Daniel Perez, Konrad Reinshagen, Caroline A Lindemans, Marcus Altfeld, Mirjam Belderbos, Thomas Dobner, Madeleine J Bunders

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

Abstract

Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1 ⁺ NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein19K, consistent with evasion from CD8 ⁺ T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1 ⁺/HLA-Bw4 ⁺ donor cells compared with children receiving non–KIR3DS1 ⁺/HLA-Bw4 ⁺ cells. These findings identify the KIR3DS1/ HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease.

Original language	English
Article number	eabe2942
Pages (from-to)	1-13
Number of pages	14
Journal	Science Immunology
Volume	6
Issue number	63
DOIs	https://doi.org/10.1126/sciimmunol.abe2942
Publication status	Published - 17 Sept 2021

Access to Document

10.1126/sciimmunol.abe2942

Cite this

Jung, J. M., Ching, W., Baumdick, M. E., Hofmann-Sieber, H., Bosse, J. B., Koyro, T., Möller, K. J., Wegner, L., Niehrs, A., Russu, K., Ohms, M., Zhang, W., Ehrhardt, A., Duisters, K., Spierings, E., Hölzemer, A., Körner, C., Jansen, S. A., Peine, S., ... Bunders, M. J. (2021). KIR3DS1 directs NK cell-mediated protection against human adenovirus infections. Science Immunology, 6(63), 1-13. Article eabe2942. https://doi.org/10.1126/sciimmunol.abe2942

@article{889bc18185bd4440b92f185b31e0909c,

title = "KIR3DS1 directs NK cell-mediated protection against human adenovirus infections",

abstract = "Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1 + NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein19K, consistent with evasion from CD8 + T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1 +/HLA-Bw4 + donor cells compared with children receiving non–KIR3DS1 +/HLA-Bw4 + cells. These findings identify the KIR3DS1/ HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease. ",

author = "Jung, {Johannes M} and Wilhelm Ching and Baumdick, {Martin E} and Helga Hofmann-Sieber and Bosse, {Jens B} and Tobias Koyro and M{\"o}ller, {Kimberly J} and Lucy Wegner and Annika Niehrs and Kristina Russu and Mareike Ohms and Wenli Zhang and Anja Ehrhardt and Kevin Duisters and Eric Spierings and Angelique H{\"o}lzemer and Christian K{\"o}rner and Jansen, {Suze A} and Sven Peine and Ingo K{\"o}nigs and Marc L{\"u}tgehetmann and Daniel Perez and Konrad Reinshagen and Lindemans, {Caroline A} and Marcus Altfeld and Mirjam Belderbos and Thomas Dobner and Bunders, {Madeleine J}",

note = "Funding Information: We thank all donors and their parents who participated in this study. We also thank the colleagues from the Department of Pediatric Surgery as well as Department of General, Visceral and Thoracic Surgery of the UKE (Hamburg) for the collection of intestinal tissues. We thank the core facility Fluorescence Cytometry and the blood donors and coordinators of the Healthy Cohort at the Leibniz Institute for Experimental Virology. We thank R. Admiraal for assistance with statistical analyses. This study is supported by the Daisy H{\"u}et Ro{\"e}ll Foundation and the German Center for Infection Research (DZIF). The Leibniz Institute for Experimental Virology is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health. J.B.B. is supported through the Cluster of Excellence RESIST (EXC 2155) under Germany{\textquoteright}s Excellence Strategy—EXC 2155—project number 390874280. A.H. is supported by the DZIF (German Center for Infection Research, TTU 01.709; 8009701709). Publisher Copyright: Copyright {\textcopyright} 2021 The Authors,",

year = "2021",

month = sep,

day = "17",

doi = "10.1126/sciimmunol.abe2942",

language = "English",

volume = "6",

pages = "1--13",

number = "63",

}

Jung, JM, Ching, W, Baumdick, ME, Hofmann-Sieber, H, Bosse, JB, Koyro, T, Möller, KJ, Wegner, L, Niehrs, A, Russu, K, Ohms, M, Zhang, W, Ehrhardt, A, Duisters, K, Spierings, E, Hölzemer, A, Körner, C, Jansen, SA, Peine, S, Königs, I, Lütgehetmann, M, Perez, D, Reinshagen, K, Lindemans, CA, Altfeld, M, Belderbos, M, Dobner, T & Bunders, MJ 2021, 'KIR3DS1 directs NK cell-mediated protection against human adenovirus infections', Science Immunology, vol. 6, no. 63, eabe2942, pp. 1-13. https://doi.org/10.1126/sciimmunol.abe2942

TY - JOUR

T1 - KIR3DS1 directs NK cell-mediated protection against human adenovirus infections

AU - Jung, Johannes M

AU - Ching, Wilhelm

AU - Baumdick, Martin E

AU - Hofmann-Sieber, Helga

AU - Bosse, Jens B

AU - Koyro, Tobias

AU - Möller, Kimberly J

AU - Wegner, Lucy

AU - Niehrs, Annika

AU - Russu, Kristina

AU - Ohms, Mareike

AU - Zhang, Wenli

AU - Ehrhardt, Anja

AU - Duisters, Kevin

AU - Spierings, Eric

AU - Hölzemer, Angelique

AU - Körner, Christian

AU - Jansen, Suze A

AU - Peine, Sven

AU - Königs, Ingo

AU - Lütgehetmann, Marc

AU - Perez, Daniel

AU - Reinshagen, Konrad

AU - Lindemans, Caroline A

AU - Altfeld, Marcus

AU - Belderbos, Mirjam

AU - Dobner, Thomas

AU - Bunders, Madeleine J

N1 - Funding Information: We thank all donors and their parents who participated in this study. We also thank the colleagues from the Department of Pediatric Surgery as well as Department of General, Visceral and Thoracic Surgery of the UKE (Hamburg) for the collection of intestinal tissues. We thank the core facility Fluorescence Cytometry and the blood donors and coordinators of the Healthy Cohort at the Leibniz Institute for Experimental Virology. We thank R. Admiraal for assistance with statistical analyses. This study is supported by the Daisy Hüet Roëll Foundation and the German Center for Infection Research (DZIF). The Leibniz Institute for Experimental Virology is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health. J.B.B. is supported through the Cluster of Excellence RESIST (EXC 2155) under Germany’s Excellence Strategy—EXC 2155—project number 390874280. A.H. is supported by the DZIF (German Center for Infection Research, TTU 01.709; 8009701709). Publisher Copyright: Copyright © 2021 The Authors,

PY - 2021/9/17

Y1 - 2021/9/17

N2 - Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1 + NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein19K, consistent with evasion from CD8 + T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1 +/HLA-Bw4 + donor cells compared with children receiving non–KIR3DS1 +/HLA-Bw4 + cells. These findings identify the KIR3DS1/ HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease.

AB - Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1 + NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein19K, consistent with evasion from CD8 + T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1 +/HLA-Bw4 + donor cells compared with children receiving non–KIR3DS1 +/HLA-Bw4 + cells. These findings identify the KIR3DS1/ HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease.

UR - http://www.scopus.com/inward/record.url?scp=85116879758&partnerID=8YFLogxK

U2 - 10.1126/sciimmunol.abe2942

DO - 10.1126/sciimmunol.abe2942

M3 - Article

C2 - 34533978

VL - 6

SP - 1

EP - 13

JO - Science Immunology

JF - Science Immunology

IS - 63

M1 - eabe2942

ER -

KIR3DS1 directs NK cell-mediated protection against human adenovirus infections

Abstract

Access to Document

Other files and links

Fingerprint

Cite this