IL-33 acts as a costimulatory signal to generate alloreactive Th1 cells in graft-versus-host disease

Gaelen K. Dwyer, Lisa R. Mathews, José A. Villegas, Anna Lucas, Anne Gonzalez de Peredo, Bruce R. Blazar, Jean Philippe Girard, Amanda C. Poholek, Sanjiv A. Luther, Warren Shlomchik, Hēth R. Turnquist

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Antigen-presenting cells (APCs) integrate signals emanating from local pathology and program appropriate T cell responses. In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases damage-associated molecular patterns (DAMPs) that generate proinflammatory APCs that secrete IL-12, which is a driver of donor Th1 responses, causing graft-versus-host disease (GVHD). Nevertheless, other mechanisms exist to initiate alloreactive T cell responses, as recipients with disrupted DAMP signaling or lacking IL-12 develop GVHD. We established that tissue damage signals are perceived directly by donor CD4+ T cells and promoted T cell expansion and differentiation. Specifically, the fibroblastic reticular cell–derived DAMP IL-33 is increased by recipient conditioning and is critical for the initial activation, proliferation, and differentiation of alloreactive Th1 cells. IL-33 stimulation of CD4+ T cells was not required for lymphopenia-induced expansion, however. IL-33 promoted IL-12–independent expression of Tbet and generation of Th1 cells that infiltrated GVHD target tissues. Mechanistically, IL-33 augmented CD4+ T cell TCR-associated signaling pathways in response to alloantigen. This enhanced T cell expansion and Th1 polarization, but inhibited the expression of regulatory molecules such as IL-10 and Foxp3. These data establish an unappreciated role for IL-33 as a costimulatory signal for donor Th1 generation after alloHCT.

Original languageEnglish (US)
Article numbere150927
JournalJournal of Clinical Investigation
Issue number12
StatePublished - Jun 15 2022

Bibliographical note

Funding Information:
Conflict of interest: BRB receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; receives research funding from BlueRock Therapeutics, Rheos Medicines, and the Childrens’ Cancer Research Fund; and is a cofounder of Tmunity Therapeutics. HRT receives renumeration as a scientific advisor to Slate Biotech and research funding from ECM Therapeutics. WS is a cofounder of, equity holder in, and paid consultant for Bluesphere Bio. Copyright: © 2022, Dwyer et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: April 29, 2021; Accepted: April 28, 2022; Published: June 15, 2022. Reference information: J Clin Invest. 2022;132(12):e150927.

Funding Information:
We acknowledge the excellent manuscript preparation by Car-la Forsythe and the technical support of Leonardo Scarpelli-no. This project used the University of Pittsburgh Genomics Research Core RNA Analysis services and Division of Laboratory Animal Resources. This work was supported by the following NIH grants: R01AR073527, R01HL22489, and R56AI139327 (to HRT); R37AI34495, R01HL56067, and R01HL11879 (to BRB); and T32CA082084 and F30AI147437 (to GKD). This work benefitted from NIH shared instrumentation grants (S10OD011925 and S10OD023402).

Publisher Copyright:
Copyright: © 2022, Dwyer et al.


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