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Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease
Holly A. Bolton, … , Elena Shklovskaya, Barbara Fazekas de St. Groth
Holly A. Bolton, … , Elena Shklovskaya, Barbara Fazekas de St. Groth
Published August 24, 2015
Citation Information: J Clin Invest. 2015;125(9):3627-3641. https://doi.org/10.1172/JCI76031.
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Research Article Immunology

Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease

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Abstract

Regulatory T cells (Tregs) have been shown to enhance immune reconstitution and prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation; however, it is unclear how Tregs mediate these effects. Here, we developed a model to examine the mechanism of Treg-dependent regulation of immune reconstitution. Lymphopenic mice were selectively reconstituted with Tregs prior to transfer of conventional CD4+ T cells. Full Treg reconstitution prevented the rapid oligoclonal proliferation that gives rise to pathogenic CD4 effector T cells, while preserving the slow homeostatic form of lymphopenia-induced peripheral expansion that repopulates a diverse peripheral T cell pool. Treg-mediated CTLA-4–dependent downregulation of CD80/CD86 on DCs was critical for inhibition of rapid proliferation and was a function of the Treg/DC ratio achieved by reconstitution. In an allogeneic BM transplant model, selective Treg reconstitution before T cell transfer also normalized DC costimulation and provided complete protection against GVHD. In contrast, cotransfer of Tregs was not protective. Our results indicate that achieving optimal recovery from lymphopenia should aim to improve early Treg reconstitution in order to increase the relative number of Tregs to DCs and thereby inhibit spontaneous oligoclonal T cell proliferation.

Authors

Holly A. Bolton, Erhua Zhu, Alexandra M. Terry, Thomas V. Guy, Woon-Puay Koh, Sioh-Yang Tan, Carl A. Power, Patrick Bertolino, Katharina Lahl, Tim Sparwasser, Elena Shklovskaya, Barbara Fazekas de St. Groth

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Figure 10

Effect of Treg reconstitution following BMT.

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Effect of Treg reconstitution following BMT.
(A) [B6.BR]F1 mice were let...
(A) [B6.BR]F1 mice were lethally irradiated and transplanted with 5 × 106 TCD B10.BR BM cells. Mice received 2.5 × 106 CD4+CD25+ Tregs from B10.BR or [B6.BR]F1 donors at the time of BMT with IL-2/JES6-1 second daily. Controls included nonirradiated (WT) mice and irradiated mice that received BM alone (BMT) or BM and IL-2/JES6-1 (BMT + IL-2) (n = 4/group). Top panel: Foxp3 and CD25 expression on total CD4+ T cells in pLN 7 days after BMT. Bottom panel: CD4+Foxp3+ Tregs were divided into host origin (CD45.2+), B10.BR donor origin (CD45.1+) and [B6.BR]F1 donor origin (CD45.1+/CD45.2+). (B) Foxp3+ Treg frequency of total CD4+ T cells (top panel), and total CD45-expressing cells (bottom panel). (C) Expression of CD80 (left) and CD86 (right) on pLN migratory DCs at day 7 after BMT. Bars represent mean ± SEM with individual values indicated by open circles. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. (D) MFI of CD80 (left panel) and CD86 (right panel) plotted against pLN Treg frequency among CD45-expressing cells. A line of best fit with R2 value is displayed. Data in A–D are representative of 2 independent experiments. (E and F) BMT recipients were administered 2.5 × 106 B10.BR CD4+CD25– T cells at day 7 after BMT. Groups included BMT recipients reconstituted with B10.BR or [B6.BR]F1 Tregs prior to T cell transfer, BMT recipients that received T cells alone, BMT recipients in which 1:1 B10.BR Tregs and T cells were cotransferred at day 7, and BMT recipients that did not receive T cells (n = 9–10/group). Shown are mouse weights (E) and a Kaplan-Meier survival analysis (F). Data are pooled from 2 independent experiments.

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