Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease.
Interleukin-15 (IL-15) is a pleiotropic proinflammatory cytokine with inefficient posttranscriptional processing. We hypothesized that endogenous IL-15 could affect disease progression in the well-described C57Bl/6 (B6)-->(C57Bl/6 x DBA/2) F1 hybrid (B6D2F1) murine model of acute allogeneic graft-versus-host disease (GVHD). B6D2F1 allogeneic recipients received transplants of IL-15(-/-) B6 bone marrow cells or B6 bone marrow cells expressing a murine IL-15 transgene (IL-15 tg) modified for efficient translation and secretion. Mice that received transplants of IL-15(-/-) B6 bone marrow cells displayed a significantly longer median survival time (MST) compared with mice that received transplants of wild-type (wt) B6 bone marrow; in contrast, mice that received transplants of IL-15 tg B6 bone marrow cells had a dramatically decreased MST. This decrease in survival was associated with a substantial activation and expansion of effector-memory (CD44highCD62Llow) CD8+ T lymphocytes. Finally, in vivo depletion of either CD4+ or CD8+ T lymphocyte subsets significantly prolonged survival in mice receiving IL-15 tg B6 marrow, while depletion of both CD4+ and CD8+ T cells provided complete protection from acute GVHD. We thus show that acute GVHD is attenuated in the absence of donor bone marrow-derived IL-15 and conclude that donor-derived IL-15 is a critical mediator of T-cell function in acute GVHD.
Blaser
Bradley W
BW
Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA.
Roychowdhury
Sameek
S
Kim
Daniel J
DJ
Schwind
Noah R
NR
Bhatt
Darshna
D
Yuan
Weifeng
W
Kusewitt
Donna F
DF
Ferketich
Amy K
AK
Caligiuri
Michael A
MA
Guimond
Martin
M
D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000401:mortality; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D002761:Cholangitis / Q000276:immunology / Q000401:mortality; D004195:Disease Models, Animal; D004751:Enteritis / Q000276:immunology / Q000401:mortality; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality; D006505:Hepatitis / Q000276:immunology / Q000401:mortality; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
D019409:Interleukin-15; D007371:Interferon-gamma