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2017 ; 8
(22
): 35542-35557
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English Wikipedia
Unique properties of thymic antigen-presenting cells promote epigenetic
imprinting of alloantigen-specific regulatory T cells
#MMPMID28415767
Garg G
; Nikolouli E
; Hardtke-Wolenski M
; Toker A
; Ohkura N
; Beckstette M
; Miyao T
; Geffers R
; Floess S
; Gerdes N
; Lutgens E
; Osterloh A
; Hori S
; Sakaguchi S
; Jaeckel E
; Huehn J
Oncotarget
2017[May]; 8
(22
): 35542-35557
PMID28415767
show ga
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.
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