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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 4

Effect of CTLA-4 expression by Tregs on modulation of CD80/CD86 and inhibition of fast-phase LIP.

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Effect of CTLA-4 expression by Tregs on modulation of CD80/CD86 and inhi...
Rag–/– hosts were reconstituted with flow-sorted WT or Ctla-4–/– Tregs. Ctla-4–/– and WT Tregs were purified from mixed BM chimeras generated with an 80:20 ratio of Ctla-4–/–/WT BM. Fully reconstituted chimeras (>3 months after irradiation) were treated with IL-2/JES6-1 at –5, –4, and –3 days to expand Treg numbers before harvest at day 0. Treg reconstitution was performed as described in Figure 1. (A) MFI of CD80 (left) and CD86 (right) on migratory DCs from pLN (n = 4 per group). Bars represent mean ± SEM with individual values indicated by the open circles. Data are from 1 of 2 independent experiments. (B) 1 × 106 CFSE-labeled WT polyclonal CD4+ T cells were transferred into Rag–/– mice, either unreconstituted or reconstituted with WT or CTLA-4–deficient Tregs (n = 3 per group). All groups were treated with second daily IL-2/JES6-1 throughout the course of the experiment. One group of Rag–/– mice reconstituted with WT Tregs received water supplemented with 5 mg/ml 1-MT from 3 days before CFSE-labeled cell transfer until organ harvest. Shown are representative CFSE division profiles from the pLN and spleen at day 7 after transfer. (C) The ratio of fully divided CFSE– T cells (>7 divisions) to CFSE+ T cells (0–3 divisions) within adoptively transferred CD4+ T cells was calculated for pLN and spleen, and summarized for all LIP experiments performed, totaling 6 independent experiments for Rag–/– and WT Treg groups, 3 experiments with Ctla-4–/– Tregs, and 2 experiments for 1-MT treatment (n = 6–19 per group). Statistical analysis was performed using one-way ANOVA with a Newman-Keuls post-test. **P < 0.01, ***P < 0.001, ****P < 0.0001.

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