Journal
BLOOD
Volume 128, Issue 3, Pages 427-439Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-12-684142
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Funding
- National Institutes of Health (NIH) National Heart, Lung, and Blood Institute [R00 HL097155, R01 HL122489, R01 HL56067, T32 HL007062]
- NIH National Institute of Allergy and Infectious Diseases [R21 AI121981, R01 AI34495, R01 HL11879, T32 AI074490]
- NIH National Institute of General Medical Sciences [T32 GM008208]
- Heisenberg Professorship [DFG ZE 872/3-1]
- DFG Einzelantrag [ZE 872/1-2]
- American Society of Transplantation/Pfizer Basic Science Faculty Development Grant
- American Society of Transplantation/Astellas Basic Science Postdoctoral Fellowship
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During allogeneic hematopoietic cell transplantation (alloHCT), nonhematopoietic cell interleukin-33 (IL-33) is augmented and released by recipient conditioning to promote type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD). Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties in the absence of coincident proinflammatory stimuli. We tested whether peri-alloHCT IL-33 delivery can protect against development of GVHD by augmenting IL-33-associated regulatory mechanisms. IL-33 administration augmented the frequency of regulatory T cells (Tregs) expressing the IL-33 receptor, suppression of tumorigenicity-2 (ST2), which persist following total body irradiation. ST2 expression is not exclusive to Tregs and IL-33 expands innate immune cells with regulatory or reparative properties. However, selective depletion of recipient Foxp3(+) cells concurrent with peri-alloHCT IL-33 administration accelerated acute GVHD lethality. IL-33-expanded Tregs protected recipients from GVHD by controlling macrophage activation and preventing accumulation of effector T cells in GVHD-target tissue. IL-33 stimulation of ST2 on Tregs activates p38 MAPK, which drives expansion of the ST2(+) Treg subset. Associated mechanistic studies revealed that proliferating Tregs exhibit IL-33-independent upregulation of ST2 and the adoptive transfer of st2(+) but not st2(-) Tregs mediated GVHD protection. In total, these data demonstrate the protective capacity of peri-alloHCT administration of IL-33 and IL-33-responsive Tregs in mouse models of acute GVHD. These findings provide strong support that the immunoregulatory relationship between IL-33 and Tregs can be harnessed therapeutically to prevent GVHD after alloHCT for treatment of malignancy or as a means for tolerance induction in solid organ transplantation.
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