Stimulation of host NKT cells by synthetic glycolipid regulates acute graft-versus-host disease by inducing Th2 polarization of donor T cells.
NKT cells are a unique immunoregulatory T cell population that produces large amounts of cytokines. We have investigated whether stimulation of host NKT cells could modulate acute graft-vs-host disease (GVHD) in mice. Injection of the synthetic NKT cell ligand alpha-galactosylceramide (alpha-GalCer) to recipient mice on day 0 following allogeneic bone marrow transplantation promoted Th2 polarization of donor T cells and a dramatic reduction of serum TNF-alpha, a critical mediator of GVHD. A single injection of alpha-GalCer to recipient mice significantly reduced morbidity and mortality of GVHD. However, the same treatment was unable to confer protection against GVHD in NKT cell-deficient CD1d knockout (CD1d(-/-)) or IL-4(-/-) recipient mice or when STAT6(-/-) mice were used as donors, indicating the critical role of host NKT cells, host production of IL-4, and Th2 cytokine responses mediated by donor T cells on the protective effects of alpha-GalCer against GVHD. Thus, stimulation of host NKT cells through administration of NKT ligand can regulate acute GVHD by inducing Th2 polarization of donor T cells via STAT6-dependent mechanisms and might represent a novel strategy for prevention of acute GVHD.
Hashimoto
Daigo
D
Biopathological Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Asakura
Shoji
S
Miyake
Sachiko
S
Yamamura
Takashi
T
Van Kaer
Luc
L
Liu
Chen
C
Tanimoto
Mitsune
M
Teshima
Takanori
T
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics; D055610:Antigens, CD1d; D016026:Bone Marrow Transplantation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000276:immunology* / Q000494:pharmacology; D006017:Glycolipids / Q000276:immunology / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D050800:STAT6 Transcription Factor; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D018949:Antigens, CD1; D055610:Antigens, CD1d; D005699:Galactosylceramides; D006017:Glycolipids; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide