Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease
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
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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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 9

Effect of Treg reconstitution on homeostatic division of T cells retaining a naive phenotype.

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Effect of Treg reconstitution on homeostatic division of T cells retaini...
(A and B) 1 × 106 CFSE-labeled conventional CD4+CD25– T cells were transferred into unreconstituted, Treg-reconstituted, or conventional T cell–reconstituted Rag–/– mice. Expression of CD44 and CD62L on donor CD4+ T cells in the pLN (n = 3 per group). Data are representative of 2 independent experiments (A). The percentage of donor CD4+ T cells that were CD44–CD62L+ (left) and CD44+CD62L– (right) was calculated (n = 5–6 per group). Data are pooled from 2 independent experiments (B). (C) 1 × 106 CFSE-labeled conventional CD4+CD25– T cells from Cd28–/– mice were adoptively transferred into unreconstituted, Treg-reconstituted, or T cell–reconstituted Rag–/– mice. Representative CFSE division profiles from pLN at day 7 after transfer are shown (left panel). The ratio of slowly dividing cells (1–3 rounds of division at day 7) to undivided cells (0 rounds of division at day 7) was calculated (right panel) (n = 6 per group). Data are pooled from 2 independent experiments. Data in B and C were analyzed using one-way ANOVA with a Newman-Keuls post-test. Bars represent mean ± SEM with individual values indicated by the open circles. **P < 0.01 and ****P < 0.0001.