SMAD3 prevents graft-versus-host disease by restraining Th1 differentiation and granulocyte-mediated tissue damage.
Gene expression profiling of human donor T cells before allogeneic hematopoietic cell transplantation revealed that expression of selected genes correlated with the occurrence of graft-versus-host disease (GVHD) in recipients. The gene with the best GVHD predictive accuracy was SMAD3, a core component of the transforming growth factor-β signaling pathway, whose expression levels vary more than a 6-fold range in humans. The putative role of SMAD3 in the establishment of graft-host tolerance remained elusive. We report that SMAD3-KO mice present ostensibly normal lymphoid and myeloid cell subsets. However, the lack of SMAD3 dramatically increased the frequency and severity of GVHD after allogeneic hematopoietic cell transplantation into major histocompatibility complex-identical recipients. Lethal GVHD induced by SMAD3-KO donors affected mainly the intestine and resulted from massive tissue infiltration by T-bet(+) CD4 T cells and granulocytes that caused tissue damage by in situ release of Th1 cytokines and oxidative-nitrosative mediators, respectively. Our report reveals the nonredundant roles of SMAD3 in the development of tolerance to the host. Furthermore, our data support the concept that SMAD3 levels in donor cells dictate the risk of GVHD and that SMAD3 agonists would be attractive for prevention of GVHD.
Institute for Research in Immunology and Cancer, Station Centre-Ville,Montreal, QC, Canada.
Martin
M
Giroux
Jean-Sébastien
JS
Delisle
Simon-David
SD
Gauthier
Krista M
KM
Heinonen
Julie
J
Hinsinger
Billy
B
Houde
Louis
L
Gaboury
Sylvie
S
Brochu
Jiangping
J
Wu
Marie-Josée
MJ
Hébert
Claude
C
Perreault
D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism*; D006410:Hematopoiesis; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D051900:Smad3 Protein / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
D051900:Smad3 Protein; C497791:Smad3 protein, mouse