Trans-presentation of donor-derived interleukin 15 is necessary for the rapid onset of acute graft-versus-host disease but not for graft-versus-tumor activity.
The "holy grail" of allogeneic stem cell transplantation is to preserve the graft-versus-tumor (GVT) effect while eliminating graft-versus-host disease (GVHD). Endogenous donor-derived interleukin 15 (IL-15) has been implicated in the pathogenesis of acute GVHD, yet the mechanism by which it impacts this lethal process remains unclear. Using the well-described and clinically relevant C57BL/6 --> B6D2F1 murine model of acute GVHD, we demonstrate that in trans presentation of IL-15 by donor bone marrow-derived cells is required for the rapid onset of acute GVHD. Recipients of IL-15-/- C57BL/6 bone marrow cells show diminished type 1 polarization of T cells, yet there is no decrease in donor T-cell reconstitution. A molecular basis for these findings is provided with the observation that expression of T-bet, the master control gene for type 1 T-cell functions, is necessary for IL-15-mediated acute GVHD lethality. Finally, we demonstrate that in the absence of donor-derived IL-15, the GVT effect is maintained. These findings thus establish a mechanism by which endogenous donor-derived IL-15 impacts the pathobiology of acute GVHD and GVT activity.
Blaser
Bradley W
BW
The Ohio State University, Comprehensive Cancer Center, A458 Starling Loving Hall, 320 W 10th Ave, Columbus, OH 43210-1214. michael.caligiuri@osumc.edu.
Schwind
Noah R
NR
Karol
Seth
S
Chang
Dennis
D
Shin
Samuel
S
Roychowdhury
Sameek
S
Becknell
Brian
B
Ferketich
Amy K
AK
Kusewitt
Donna F
DF
Blazar
Bruce R
BR
Caligiuri
Michael A
MA
D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000175:diagnosis* / Q000378:metabolism; D020350:Graft vs Tumor Effect; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000378:metabolism; D014184:Transplantation, Homologous
D019409:Interleukin-15