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

• Published in: Journal of Clinical Investigation 2022, Vol.132 (12)
• Main Authors: Dwyer, Gaelen K, Mathews, Lisa R, Villegas, Jose A, Lucas, Anna, de Peredo, Anne Gonzalez, Blazar, Bruce R, Girard, Jean-Philippe, Poholek, Amanda C, Luther, Sanjiv A, Shlomchik, Warren, Turnquist, Heth R
• Format: Report
• Language: English
• Subjects: Antigen presenting cells; Care and treatment; Cellular signal transduction; Development and progression; Graft versus host reaction; Health aspects; Hematopoietic stem cells; Immunological research; Interleukins; Physiological aspects; Stem cells; T cells; Transplantation
• ISSN: 0021-9738
• DOI: 10.1172/JCI150927

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.sup.+] 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.sup.+] 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.sup.+] 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.