The Journal of Clinical Investigation (Jun 2022)

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

Journal volume & issue
Vol. 132, no. 12

Abstract

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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.

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