Unique Properties of Thymic Antigen-presenting Cells Promote Epigenetic Imprinting of Alloantigen-specific Regulatory T Cells

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Apr 19

PMID 28415767

Citations 14

Authors

Garima Garg

Eirini Nikolouli

Matthias Hardtke-Wolenski

Aras Toker

Naganari Ohkura

Michael Beckstette

Takahisa Miyao

Robert Geffers

Stefan Floess

Norbert Gerdes

Esther Lutgens

Anke Osterloh

Shohei Hori

Shimon Sakaguchi

Elmar Jaeckel

Jochen Huehn

Affiliations

Soon will be listed here.

Abstract

Regulatory T cells (Tregs) are potential immunotherapeutic candidates to induce transplantation tolerance. However, stability of Tregs still remains contentious and may potentially restrict their clinical use. Recent work suggested that epigenetic imprinting of Foxp3 and other Treg-specific signature genes is crucial for stabilization of immunosuppressive properties of Foxp3+ Tregs, and that these events are initiated already during early stages of thymic Treg development. However, the mechanisms governing this process remain largely unknown. Here we demonstrate that thymic antigen-presenting cells (APCs), including thymic dendritic cells (t-DCs) and medullary thymic epithelial cells (mTECs), can induce a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signature genes in developing Tregs when compared to splenic DCs (sp-DCs). Transcriptomic profiling of APCs revealed differential expression of secreted factors and costimulatory molecules, however neither addition of conditioned media nor interference with costimulatory signals affected Foxp3 induction by thymic APCs in vitro. Importantly, when tested in vivo both mTEC- and t-DC-generated alloantigen-specific Tregs displayed significantly higher efficacy in prolonging skin allograft acceptance when compared to Tregs generated by sp-DCs. Our results draw attention to unique properties of thymic APCs in initiating commitment towards stable and functional Tregs, a finding that could be highly beneficial in clinical immunotherapy.

Citing Articles

Evaluating approaches for studying the roles of thymic DCs in T cell development in mice.

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Treg-based immunotherapy for antigen-specific immune suppression and stable tolerance induction: a perspective.

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Stepwise acquisition of unique epigenetic signatures during differentiation of tissue Treg cells.

Braband K, Kaufmann T, Floess S, Zou M, Huehn J, Delacher M Front Immunol. 2022; 13:1082055.

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The thymic microenvironment gradually modulates the phenotype of thymus-homing peripheral conventional dendritic cells.

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