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.
View: Text | PDF
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

×

Figure 2

GVHD causes loss of DC progenitors.

Options: View larger image (or click on image) Download as PowerPoint
GVHD causes loss of DC progenitors. (A and B) B6 TCD-BM (5 × 106 cells) ...
(A and B) 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. (A) Percentages and number of MPPs and CDPs in the BM from normal, TCD-BM, and T cell recipients; each group contained 4 to 10 mice pooled from at least 3 independent experiments. (B) MPPs and CDPs were isolated by FACS from normal and GVHD mice (CD45.2+) and cultured with feeder cells (BM from B6/SJL mice, CD45.1+) in the presence of Flt3L plus SCF. MPPs and CDPs were cultured for 9 days and 3 days, respectively. Percentages and numbers of pDCs were measured. (C and D) BM cells were obtained from HD and allo-HSCT patients. (C) Plots show pDC and cDC gating strategy. Plots show phenotypes of human CD34+ HSPCs from HD (n = 12), grade 0–I GVHD patients (n = 7), and grade II–IV GVHD patients (n = 8). (D) Graphs show the percentages of human MPPs and CDPs from healthy donors (HD) (n = 12), grade 0–I GVHD patients (n = 8), and grade II–IV GVHD patients (n = 9). Multiple comparisons were evaluated by 1-way ANOVA with Bonferroni’s multiple-comparison test (A), 2-group comparisons by unpaired t test (2-tailed) (B), and multiple comparisons by Kruskal-Wallis test with Dunn’s multiple-comparison test (D). Data shown are mean ± SD. Results shown in A and B are representative of 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001.