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.
View: Text | PDF
Research Article Immunology

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

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

×

Figure 6

Effect of expansion of Treg populations in immunosufficient mice on DC costimulation and T cell proliferation.

Options: View larger image (or click on image) Download as PowerPoint
Effect of expansion of Treg populations in immunosufficient mice on DC c...
WT mice were treated with IL-2/JES6-1 complexes at days 0, 1, and 2, and lymphoid organs were harvested at day 5. (A) Representative plots of Foxp3 versus CD25 expression by CD4+ T cells from pLN and spleen. Numbers indicate the percentage of cells within the gate. (B) Absolute number of Foxp3+ Tregs in pLN and spleen of untreated versus IL-2/JES6-1–treated WT mice. (C) MFI of CD80 and CD86 expression by migratory DCs in pLN (left panels) and CD8+ and CD11b+ subsets of splenic DCs (right panels). Data in A–C are representative of 3 independent experiments with n = 5 per group. (D) Proliferation of adoptively transferred 5C.C7 T cells in response to 1 μg i.v. peptide in WT hosts pretreated with IL-2/JES6-1 complexes at days –5, –4, and –3. Left panel: representative CFSE division profiles from pLN and spleen at day 3 after T cell transfer for IL-2/JES6-1 treated hosts (unfilled histograms) compared with untreated WT hosts (filled histograms). Right panel: MFI of CFSE expression by adoptively transferred 5C.C7 T cells (n = 5 mice per group). Data are from a single experiment. Statistical analysis of B–D was performed using 2-tailed unpaired t tests. Bars represent mean ± SEM with individual values indicated by the open circles. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.