Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD

Benjamin M. Matta, Dawn K. Reichenbach, Xiaoli Zhang, Lisa Mathews, Brent H. Koehn, Gaelen K. Dwyer, Jeremy M. Lott, Franziska M. Uhl, Dietmar Pfeifer, Colby J. Feser, Michelle J. Smith, Quan Liu, Robert Zeiser, Bruce R. Blazar, Heth R. Turnquist

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)427-439
Number of pages13
Issue number3
StatePublished - Jul 21 2016

Bibliographical note

Funding Information:
The authors acknowledge the Unified Flow Cytometry Core Facility at the University of Pittsburgh for their expertise and assistance. The authors thank Rosemary Hoffman for expertise and help with LPL isolation, as well as members of Angus W. Thomson's laboratory for assistance with thymidine incorporation assays. This work was supported by National Institutes of Health (NIH) National Heart, Lung, and Blood Institute grants R00 HL097155 (H.R.T.), R01 HL122489 (H.R.T.), R01 HL56067 (B.R.B.), and T32 HL007062 (D.K.R.) and NIH National Institute of Allergy and Infectious Diseases grants R21 AI121981 (H.R.T.), R01 AI34495 (B.R.B.), R01 HL11879 (B.R.B.), and T32 AI074490 (B.M.M.). G.K.D. was supported by a grant from the NIH National Institute of General Medical Sciences (T32 GM008208). Further support was provided by the Heisenberg Professorship (DFG ZE 872/3-1) and DFG Einzelantrag (ZE 872/1-2) (R.Z.), an American Society of Transplantation/Pfizer Basic Science Faculty Development Grant (H.R.T.), and an American Society of Transplantation/Astellas Basic Science Postdoctoral Fellowship (B.M.M.).

Publisher Copyright:
© 2016 by The American Society of Hematology.


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