Abstract
Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.
Original language | English (US) |
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Pages (from-to) | 384-393 |
Number of pages | 10 |
Journal | Journal of Immunology |
Volume | 213 |
Issue number | 3 |
DOIs | |
State | Published - Aug 1 2024 |
Keywords
- Animals
- Dendritic Cells/immunology
- Graft vs Host Disease/immunology
- Mice
- Endoplasmic Reticulum Stress/immunology
- Protein Serine-Threonine Kinases/genetics
- Endoribonucleases/genetics
- X-Box Binding Protein 1/genetics
- Mice, Knockout
- Mice, Inbred C57BL
- Hematopoietic Stem Cell Transplantation
- Bone Marrow Transplantation
- Signal Transduction
- Cell Differentiation/immunology
- Graft vs Leukemia Effect/immunology
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology