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- Title
Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction.
- Authors
Yuanyuan Tian; Lijun Meng; Ying Wang; Bohan Li; Hongshuang Yu; Yan Zhou; Tien Bui; Abraham, Ciril; Li, Alicia; Yongping Zhang; Jian Wang; Chenchen Zhao; Shin Mineishi; Gallucci, Stefania; Porter, David; Hexner, Elizabeth; Hong Zheng; Yanyun Zhang; Shaoyan Hu; Yi Zhang
- Abstract
Graft-versus-host disease (GVHD) causes failed reconstitution of donor plasmacytoid dendritic cells (pDCs) that are critical for immune protection and tolerance. We used both murine and human systems to uncover the mechanisms whereby GVHD induces donor pDC defects. GVHD depleted Flt3-expressing donor multipotent progenitors (MPPs) that sustained pDCs, leading to impaired generation of pDCs. MPP loss was associated with decreased amounts of MPP-producing hematopoietic stem cells (HSCs) and oxidative stress-induced death of proliferating MPPs. Additionally, alloreactive T cells produced GM-CSF to inhibit MPP expression of Tcf4, the transcription factor essential for pDC development, subverting MPP production of pDCs. GM-CSF did not affect the maturation of pDC precursors. Notably, enhanced recovery of donor pDCs upon adoptive transfer early after allogeneic HSC transplantation repressed GVHD and restored the de novo generation of donor pDCs in recipient mice. pDCs suppressed the proliferation and expansion of activated autologous T cells via a type I IFN signaling-dependent mechanism. They also produced PD-L1 and LILRB4 to inhibit T cell production of IFN-γ. We thus demonstrate that GVHD impairs the reconstitution of tolerogenic donor pDCs by depleting DC progenitors rather than by preventing pDC maturation. MPPs are an important target to effectively bolster pDC reconstitution for controlling GVHD.
- Subjects
GRAFT versus host disease; PROGENITOR cells; DENDRITIC cells; HEMATOPOIETIC stem cells; T cells; IMMUNOLOGICAL tolerance; RESEARCH; ANIMAL experimentation; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; STEM cells; RESEARCH funding; MICE
- Publication
Journal of Clinical Investigation, 2021, Vol 131, Issue 1, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI136774