SOCS3 regulates graft-versus-host disease.
Suppressor of cytokine signaling-3 (SOCS3) is the main intracellular regulator of signaling by granulocyte colony-stimulating factor, an immune-modulatory cytokine used to mobilize stem cells for transplantation. We have therefore studied the contribution of SOCS3 to the spectrum of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Grafts from SOCS3(-/Deltavav) donor mice in which SOCS3 deficiency is restricted to the hematopoietic compartment had an augmented capacity to induce acute GVHD. With the use of SOCS3(-/DeltaLysM) and SOCS3(-/Deltalck) donors in which SOCS3 deficiency was restricted to the myeloid or T-cell lineage, respectively, we confirmed SOCS3 deficiency promoted acute GVHD mortality and histopathology within the gastrointestinal tract by effects solely within the donor T cell. SOCS3(-/Deltalck) donor T cells underwent enhanced alloantigen-dependent proliferation and generation of interleukin-10 (IL-10), IL-17, and interferon-gamma (IFNgamma) after SCT. The enhanced capacity of the SOCS3(-/Deltalck) donor T cell to induce acute GVHD was dependent on IFNgamma but independent of IL-10 or IL-17. Surprisingly, SOCS3(-/Deltalck) donor T cells also induced severe, transforming growth factor beta- and IFNgamma-dependent, sclerodermatous GVHD. Thus, the delivery of small molecule SOCS3 mimetics may prove to be useful for the inhibition of both acute and chronic GVHD.
Hill
Geoffrey R
GR
The Queensland Institute of Medical Research, 300 Herston Rd., Brisbane, Queensland 4006, Australia.
Kuns
Rachel D
RD
Raffelt
Neil C
NC
Don
Alistair L J
AL
Olver
Stuart D
SD
Markey
Kate A
KA
Wilson
Yana A
YA
Tocker
Joel
J
Alexander
Warren S
WS
Clouston
Andrew D
AD
Roberts
Andrew W
AW
MacDonald
Kelli P A
KP
D000818:Animals; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous
D016207:Cytokines; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins