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

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 3

Correlation between Treg/DC ratio, DC costimulation, and spontaneous T cell proliferation.

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Correlation between Treg/DC ratio, DC costimulation, and spontaneous T c...
(A) MFI of CD80 and CD86 on migratory DCs in pLN (filled circle) and mLN (open circle) of Rag–/– mice at day 7 after reconstitution with 0.25 × 106, 0.5 × 106, 1 × 106, or 2.5 × 106 Treg (n = 4 per group). To allow for comparison between organs in which DCs express CD80/CD86 at different levels, expression of CD80/CD86 in individual pLN or mLN in Figure 2C was normalized against the mean WT expression level and then plotted against Treg frequency in the individual LN. A line of best fit with R2 value is displayed. (B) To allow for comparison between organs in which both costimulation and DC number differed, total expression of CD80/CD86 in individual LN and spleen was calculated by multiplying MFI CD80 or CD86 by the number of DCs in the relevant organ and normalized against the WT mean. The Treg/DC ratio was also normalized against the WT mean ratio. (C) To compare expression of CD80/CD86 with the extent of fast-phase LIP, the ratio of CFSE– (>7 divisions) to CFSE+ (0–3 divisions) T cells in the pLN and mLN at day 7 after transfer (Figure 1) was normalized against the ratio in Rag–/– mice and plotted against migratory DC expression of CD80/CD86 (Figure 2, normalized against Rag–/– expression) at the time of T cell transfer. A semilog curve with R2 value is displayed. For A and B, broken lines indicate mean WT levels of costimulation/Treg/DC ratio, while in C, broken lines indicate mean Rag–/– levels of costimulation/T cell proliferation.