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 8

Effect of Treg depletion in immunosufficient animals on expression of costimulation.

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Effect of Treg depletion in immunosufficient animals on expression of co...
(A and B) DEREG mice were treated with 1 μg DT i.p. at days 0 and 1. MFI of CD80 (upper panels) and CD86 expression (lower panels) by migratory DCs from pLN (left) or splenic DCs (right; unbroken lines) graphed against Tregs as a percentage of CD4+ T cells (dotted lines) between days 0 and 3 (A), and at days 0 and 3–7 (B). Data in A and B are mean ± SEM (n = 3–4 per group) and are each from a single experiment. (C) WT mice were treated with 500 μg anti-CD25 (clone PC61) 18 hours before harvest of spleens. Controls received either PBS, or 500 μg of anti-Vα11 (clone RR8) (n = 2–4 per group). MFI of CD80 and CD86 expression by unfractionated CD11c+B220– splenic DCs from a single experiment is shown. (D) WT mice were irradiated with 700 cGy, and spleens were harvested at 0, 3, or 24 hours. MFI of CD80 and CD86 expression by unfractionated CD11c+B220– splenic DCs is shown (n = 5–7 per group). Data are from a single experiment. Statistical analysis of A–D was performed using one-way ANOVA with a Newman-Keuls post-test. 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.