Invariant natural killer T cell-natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration

Rachel D. Kuns, Edward S. Morris, Kelli P A MacDonald, Kate A. Markey, Helen M. Morris, Neil C. Raffelt, Tatjana Banovic, Alistair L J Don, Vanessa Rowe, Angela C. Burman, Andrew D. Clouston, Camile Farah, Gurdyal S. Besra, Petr A. Illarionov, Mark J. Smyth, Steven A. Porcelli, Geoffrey R. Hill

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the α-galactosylceramide [α-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified α-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)-dependent natural killer (NK)- and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC-NK-cell interaction and raise concern for the use of α-GalCer therapeutically to modulate GVHD and GVL effects.

Original languageEnglish (US)
Pages (from-to)5999-6010
Number of pages12
JournalBlood
Volume113
Issue number23
DOIs
StatePublished - 2009

Fingerprint

Galactosylceramides
Natural Killer T-Cells
T-cells
Graft vs Host Disease
Grafts
Cell Communication
Natural Killer Cells
Transplantation
Leukemia
Transplants
Interleukin-12
Dendritic Cells
Chemical activation
Glycolipids
Stem Cell Transplantation
Adaptive Immunity
T-Cell Antigen Receptor
Innate Immunity
Transplantation (surgical)
Mortality

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Kuns, R. D., Morris, E. S., MacDonald, K. P. A., Markey, K. A., Morris, H. M., Raffelt, N. C., ... Hill, G. R. (2009). Invariant natural killer T cell-natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration. Blood, 113(23), 5999-6010. https://doi.org/10.1182/blood-2008-10-183335

Invariant natural killer T cell-natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration. / Kuns, Rachel D.; Morris, Edward S.; MacDonald, Kelli P A; Markey, Kate A.; Morris, Helen M.; Raffelt, Neil C.; Banovic, Tatjana; Don, Alistair L J; Rowe, Vanessa; Burman, Angela C.; Clouston, Andrew D.; Farah, Camile; Besra, Gurdyal S.; Illarionov, Petr A.; Smyth, Mark J.; Porcelli, Steven A.; Hill, Geoffrey R.

In: Blood, Vol. 113, No. 23, 2009, p. 5999-6010.

Research output: Contribution to journalArticle

Kuns, RD, Morris, ES, MacDonald, KPA, Markey, KA, Morris, HM, Raffelt, NC, Banovic, T, Don, ALJ, Rowe, V, Burman, AC, Clouston, AD, Farah, C, Besra, GS, Illarionov, PA, Smyth, MJ, Porcelli, SA & Hill, GR 2009, 'Invariant natural killer T cell-natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration', Blood, vol. 113, no. 23, pp. 5999-6010. https://doi.org/10.1182/blood-2008-10-183335
Kuns, Rachel D. ; Morris, Edward S. ; MacDonald, Kelli P A ; Markey, Kate A. ; Morris, Helen M. ; Raffelt, Neil C. ; Banovic, Tatjana ; Don, Alistair L J ; Rowe, Vanessa ; Burman, Angela C. ; Clouston, Andrew D. ; Farah, Camile ; Besra, Gurdyal S. ; Illarionov, Petr A. ; Smyth, Mark J. ; Porcelli, Steven A. ; Hill, Geoffrey R. / Invariant natural killer T cell-natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration. In: Blood. 2009 ; Vol. 113, No. 23. pp. 5999-6010.
@article{daf4b2b439494ea4add3a02a4f7bd8f0,
title = "Invariant natural killer T cell-natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration",
abstract = "Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the α-galactosylceramide [α-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified α-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)-dependent natural killer (NK)- and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC-NK-cell interaction and raise concern for the use of α-GalCer therapeutically to modulate GVHD and GVL effects.",
author = "Kuns, {Rachel D.} and Morris, {Edward S.} and MacDonald, {Kelli P A} and Markey, {Kate A.} and Morris, {Helen M.} and Raffelt, {Neil C.} and Tatjana Banovic and Don, {Alistair L J} and Vanessa Rowe and Burman, {Angela C.} and Clouston, {Andrew D.} and Camile Farah and Besra, {Gurdyal S.} and Illarionov, {Petr A.} and Smyth, {Mark J.} and Porcelli, {Steven A.} and Hill, {Geoffrey R.}",
year = "2009",
doi = "10.1182/blood-2008-10-183335",
language = "English (US)",
volume = "113",
pages = "5999--6010",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "23",

}

TY - JOUR

T1 - Invariant natural killer T cell-natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration

AU - Kuns, Rachel D.

AU - Morris, Edward S.

AU - MacDonald, Kelli P A

AU - Markey, Kate A.

AU - Morris, Helen M.

AU - Raffelt, Neil C.

AU - Banovic, Tatjana

AU - Don, Alistair L J

AU - Rowe, Vanessa

AU - Burman, Angela C.

AU - Clouston, Andrew D.

AU - Farah, Camile

AU - Besra, Gurdyal S.

AU - Illarionov, Petr A.

AU - Smyth, Mark J.

AU - Porcelli, Steven A.

AU - Hill, Geoffrey R.

PY - 2009

Y1 - 2009

N2 - Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the α-galactosylceramide [α-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified α-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)-dependent natural killer (NK)- and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC-NK-cell interaction and raise concern for the use of α-GalCer therapeutically to modulate GVHD and GVL effects.

AB - Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the α-galactosylceramide [α-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified α-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)-dependent natural killer (NK)- and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC-NK-cell interaction and raise concern for the use of α-GalCer therapeutically to modulate GVHD and GVL effects.

UR - http://www.scopus.com/inward/record.url?scp=67651115861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651115861&partnerID=8YFLogxK

U2 - 10.1182/blood-2008-10-183335

DO - 10.1182/blood-2008-10-183335

M3 - Article

C2 - 19369232

AN - SCOPUS:67651115861

VL - 113

SP - 5999

EP - 6010

JO - Blood

JF - Blood

SN - 0006-4971

IS - 23

ER -