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 - 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 - https://www.scopus.com/pages/publications/85014835577
UR - https://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 -
