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 3

GVHD impairs both the quantity and quality of MPPs that sustain pDCs.

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GVHD impairs both the quantity and quality of MPPs that sustain pDCs. HS...
HSCs (CD150+CD48– LSK cells), MPPs, and CDPs were isolated by FACS from the BM of normal mice (A) and cultured in the presence of Flt3L plus SCF to induce pDC generation (B). (C) Plots show Flt3 expression on the surface of MPPs. (D) Generation of pDCs from Flt3hi MPPs and Flt3mod MPPs in cultures stimulated with Flt3L plus SCF. (E) Proliferation capacity of Flt3hi MPPs and Flt3mod MPPs in vivo indicated by BrdU. (F) Real-time RT-PCR assay revealed the relative expression of indicated genes in freshly isolated Flt3hi MPPs and Flt3mod MPPs (mean ± SD). (G–I) B6 TCD-BM (5 × 106 cells) was transplanted with or without CD4+ T cells (5 × 105) into lethally irradiated BALB/c mice to induce GVHD. BM cells were recovered from these mice 21 days after transplantation. Plots show the fraction of Flt3hi MPPs and Flt3mod MPPs in the BM of normal and GVHD mice (n = 5 per group) (G) and graphs show the frequency and numbers of BM of Flt3hi MPPs and Flt3mod MPPs (H). (I) Flt3mod MPPs were sorted from the BM of normal and GVHD mice and cultured in the presence of Flt3 plus SCF for 9 days. Graphs show the percentage and number of pDCs and cDCs derived from the culture. Data shown are mean ± SD. Results are representative of at least 2 independent experiments, with triplicates in each group. Multiple comparisons were evaluated by 1-way ANOVA together with Bonferroni’s multiple-comparison test (B and H), and 2-group comparisons by 2-tailed unpaired t tests (D–F and I). *P < 0.05; **P < 0.01; ***P < 0.001.