GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity

Mark D. Bunting; Antiopi Varelias; Fernando Souza-Fonseca-Guimaraes; Iona S. Schuster; Katie E. Lineburg; Rachel D. Kuns; Peter Fleming; Kelly R. Locke; Nicholas D. Huntington; Bruce R. Blazar; Steven W. Lane; Siok Keen Tey; Kelli P A MacDonald; Mark J. Smyth; Mariapia A. Degli-Esposti; Geoffrey R. Hill

doi:10.1182/blood-2016-08-734020

GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity

Mark D. Bunting, Antiopi Varelias, Fernando Souza-Fonseca-Guimaraes, Iona S. Schuster, Katie E. Lineburg, Rachel D. Kuns, Peter Fleming, Kelly R. Locke, Nicholas D. Huntington, Bruce R. Blazar, Steven W. Lane, Siok Keen Tey, Kelli P A MacDonald, Mark J. Smyth, Mariapia A. Degli-Esposti, Geoffrey R. Hill

Administration (TMED)

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

30 Scopus citations

Abstract

Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graft-versus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Rα or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects. Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity.

Original language	English (US)
Pages (from-to)	630-642
Number of pages	13
Journal	Blood
Volume	129
Issue number	5
DOIs	https://doi.org/10.1182/blood-2016-08-734020
State	Published - Feb 2 2017

Bibliographical note

Funding Information:
The authors acknowledge Michelle Teng for her critical reading of the manuscript. This work was supported by research grants from the National Health and Medical Research Council (NHandMRC). F.S.-F.-G. was supported by a NHandMRC Early Career Research Fellowship and National Breast Cancer Foundation Fellowship. S.W.L. was supported by a NHandMRC Career Development Fellowship. M.A.D.-E. was a NHandMRC Principal Research Fellow. M.J.S. and G.R.H. were NHandMRC Senior Principal Research Fellows. G.R.H. was a QLD Health Senior Clinical Research Fellow. B.R.B. was supported by National Institutes of Health National Cancer Institute grant R01 CA72669.

Publisher Copyright:
© 2017 by The American Society of Hematology.

UN SDGs

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

Access

10.1182/blood-2016-08-734020

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290987

OpenUrl availability

Full text

Cite this

Bunting, M. D., Varelias, A., Souza-Fonseca-Guimaraes, F., Schuster, I. S., Lineburg, K. E., Kuns, R. D., Fleming, P., Locke, K. R., Huntington, N. D., Blazar, B. R., Lane, S. W., Tey, S. K., MacDonald, K. P. A., Smyth, M. J., Degli-Esposti, M. A., & Hill, G. R. (2017). GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity. Blood, 129(5), 630-642. https://doi.org/10.1182/blood-2016-08-734020

Bunting, MD, Varelias, A, Souza-Fonseca-Guimaraes, F, Schuster, IS, Lineburg, KE, Kuns, RD, Fleming, P, Locke, KR, Huntington, ND, Blazar, BR, Lane, SW, Tey, SK, MacDonald, KPA, Smyth, MJ, Degli-Esposti, MA & Hill, GR 2017, 'GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity', Blood, vol. 129, no. 5, pp. 630-642. https://doi.org/10.1182/blood-2016-08-734020

@article{5df8bfa190964596b7ca65b04449f372,

title = "GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity",

abstract = "Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graft-versus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Rα or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects. Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity.",

author = "Bunting, {Mark D.} and Antiopi Varelias and Fernando Souza-Fonseca-Guimaraes and Schuster, {Iona S.} and Lineburg, {Katie E.} and Kuns, {Rachel D.} and Peter Fleming and Locke, {Kelly R.} and Huntington, {Nicholas D.} and Blazar, {Bruce R.} and Lane, {Steven W.} and Tey, {Siok Keen} and MacDonald, {Kelli P A} and Smyth, {Mark J.} and Degli-Esposti, {Mariapia A.} and Hill, {Geoffrey R.}",

note = "Funding Information: The authors acknowledge Michelle Teng for her critical reading of the manuscript. This work was supported by research grants from the National Health and Medical Research Council (NHandMRC). F.S.-F.-G. was supported by a NHandMRC Early Career Research Fellowship and National Breast Cancer Foundation Fellowship. S.W.L. was supported by a NHandMRC Career Development Fellowship. M.A.D.-E. was a NHandMRC Principal Research Fellow. M.J.S. and G.R.H. were NHandMRC Senior Principal Research Fellows. G.R.H. was a QLD Health Senior Clinical Research Fellow. B.R.B. was supported by National Institutes of Health National Cancer Institute grant R01 CA72669. Publisher Copyright: {\textcopyright} 2017 by The American Society of Hematology.",

year = "2017",

month = feb,

day = "2",

doi = "10.1182/blood-2016-08-734020",

language = "English (US)",

volume = "129",

pages = "630--642",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "5",

}

TY - JOUR

T1 - GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity

AU - Bunting, Mark D.

AU - Varelias, Antiopi

AU - Souza-Fonseca-Guimaraes, Fernando

AU - Schuster, Iona S.

AU - Lineburg, Katie E.

AU - Kuns, Rachel D.

AU - Fleming, Peter

AU - Locke, Kelly R.

AU - Huntington, Nicholas D.

AU - Blazar, Bruce R.

AU - Lane, Steven W.

AU - Tey, Siok Keen

AU - MacDonald, Kelli P A

AU - Smyth, Mark J.

AU - Degli-Esposti, Mariapia A.

AU - Hill, Geoffrey R.

N1 - Funding Information: The authors acknowledge Michelle Teng for her critical reading of the manuscript. This work was supported by research grants from the National Health and Medical Research Council (NHandMRC). F.S.-F.-G. was supported by a NHandMRC Early Career Research Fellowship and National Breast Cancer Foundation Fellowship. S.W.L. was supported by a NHandMRC Career Development Fellowship. M.A.D.-E. was a NHandMRC Principal Research Fellow. M.J.S. and G.R.H. were NHandMRC Senior Principal Research Fellows. G.R.H. was a QLD Health Senior Clinical Research Fellow. B.R.B. was supported by National Institutes of Health National Cancer Institute grant R01 CA72669. Publisher Copyright: © 2017 by The American Society of Hematology.

PY - 2017/2/2

Y1 - 2017/2/2

N2 - Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graft-versus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Rα or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects. Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity.

AB - Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graft-versus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Rα or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects. Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity.

UR - http://www.scopus.com/inward/record.url?scp=85014835577&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014835577&partnerID=8YFLogxK

U2 - 10.1182/blood-2016-08-734020

DO - 10.1182/blood-2016-08-734020

M3 - Article

C2 - 27927647

AN - SCOPUS:85014835577

SN - 0006-4971

VL - 129

SP - 630

EP - 642

JO - Blood

JF - Blood

IS - 5

ER -

GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity

Abstract

Bibliographical note

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this