IL-33 acts as a costimulatory signal to generate alloreactive Th1 cells in graft-versus-host disease.
Details
Serval ID
serval:BIB_9A7DBCB96AD9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
IL-33 acts as a costimulatory signal to generate alloreactive Th1 cells in graft-versus-host disease.
Journal
Journal of clinical investigation
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Publication state
Published
Issued date
15/06/2022
Peer-reviewed
Oui
Volume
132
Number
12
Pages
e150927
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
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.
Keywords
Animals, Bone Marrow Transplantation/adverse effects, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation/adverse effects, Humans, Interleukin-12, Interleukin-33/genetics, Mice, Mice, Inbred BALB C, Th1 Cells/pathology, Bone marrow transplantation, Costimulation, Immunology, Th1 response, Transplantation
Pubmed
Web of science
Open Access
Yes
Create date
16/05/2022 7:46
Last modification date
23/01/2024 7:31