Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction
Yuanyuan Tian, … , Shaoyan Hu, Yi Zhang
Yuanyuan Tian, … , Shaoyan Hu, Yi Zhang
Published October 22, 2020
Citation Information: J Clin Invest. 2021;131(1):e136774. https://doi.org/10.1172/JCI136774.
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Research Article

Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction

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.

Authors

Yuanyuan Tian, Lijun Meng, Ying Wang, Bohan Li, Hongshuang Yu, Yan Zhou, Tien Bui, Ciril Abraham, Alicia Li, Yongping Zhang, Jian Wang, Chenchen Zhao, Shin Mineishi, Stefania Gallucci, David Porter, Elizabeth Hexner, Hong Zheng, Yanyun Zhang, Shaoyan Hu, Yi Zhang

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Figure 4

LT-HSCs are decreased in GVHD but retain the capacity to produce MPPs.

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LT-HSCs are decreased in GVHD but retain the capacity to produce MPPs. B...
B6 TCD-BM, together with or without T cells, was transferred into lethally irradiated BALB/c mice. (A and B) Flt3– LSK cells were highly purified from the BM of normal and GVHD mice 21 days after transplantation. RNA was extracted from these HSPCs for RNA-seq analysis. (A) Heatmap shows genes differentially expressed in normal and GVHD Flt3– LSK cells. (B) Gene set enrichment analysis of the characteristics of genes associated with HSCs. (C–F) BM cells from normal, TCD-BM recipients, and T cell recipients were stained with a panel of antibodies that recognize stem cells. (C) Percentage and numbers of LT-HSCs in the BM were examined. (D) LT-HSCs (CD45.2+) were purified from the BM of normal and GVHD mice 21 days after transplantation and adoptively transferred into sublethally irradiated B6/SJL mice. (E and F) After an additional 15 and 34 days, cells from the BM of these secondary recipients were examined to monitor the regeneration of HSCs and Flt3+ MPPs. Multiple comparisons were evaluated by 1-way ANOVA with Bonferroni’s multiple-comparison test (D–F). Data shown are mean ± SD. Results shown in C–F are representative of at least 2 independent experiments. *P < 0.05; ***P < 0.001.