Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease.
Th17 is a newly identified T-cell lineage that secretes proinflammatory cytokine IL-17. Th17 cells have been shown to play a critical role in mediating autoimmune diseases such as EAE, colitis, and arthritis, but their role in the pathogenesis of graft-versus-host disease (GVHD) is still unknown. Here we showed that, in an acute GVHD model of C57BL/6 (H-2(b)) donor to BALB/c (H-2(d)) recipient, IL-17(-/-) donor T cells manifested an augmented Th1 differentiation and IFN-gamma production and induced exacerbated acute GVHD. Severe tissue damage mediated by IL-17(-/-) donor T cells was associated with increased Th1 infiltration, up-regulation of chemokine receptors by donor T cells, and enhanced tissue expression of inflammatory chemokines. Administration of recombinant IL-17 and neutralizing IFN-gamma in the recipients given IL-17(-/-) donor cells ameliorated the acute GVHD. Furthermore, the regulation of Th1 differentiation by IL-17 or Th17 may be through its influence on host DCs. Our results indicate that donor Th17 cells can down-regulate Th1 differentiation and ameliorate acute GVHD in allogeneic recipients, and that treatments neutralizing proinflammatory cytokine IL-17 may augment acute GVHD as well as other inflammatory autoimmune diseases.
Yi
Tangsheng
T
Graduate School of Biological Science, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Zhao
Dongchang
D
Lin
Chia-Lei
CL
Zhang
Chunyan
C
Chen
Ying
Y
Todorov
Ivan
I
LeBon
Thomas
T
Kandeel
Fouad
F
Forman
Stephen
S
Zeng
Defu
D
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D018925:Chemokines / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D020381:Interleukin-17 / Q000008:administration & dosage / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009500:Neutralization Tests; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology*; D014019:Tissue Donors; D014184:Transplantation, Homologous
D018925:Chemokines; D017931:DNA Primers; D020381:Interleukin-17; D007371:Interferon-gamma