Induction of antigen-specific regulatory T lymphocytes by human dendritic cells expressing the glucocorticoid-induced leucine zipper.
Dendritic cells (DCs) determine whether antigen presentation leads to immune activation or to tolerance. Tolerance-inducing DCs (also called regulatory DCs) act partly by generating regulatory T lymphocytes (Tregs). The mechanism used by DCs to switch toward regulatory DCs during their differentiation is unclear. We show here that human DCs treated in vitro with glucocorticoids produce the glucocorticoid-induced leucine zipper (GILZ). Antigen presentation by GILZ-expressing DCs generates CD25(high)FOXP3(+)CTLA-4/CD152(+) and interleukin-10-producing Tregs inhibiting the response of CD4(+) and CD8(+) T lymphocytes. This inhibition is specific to the antigen presented, and only proliferating CD4(+) T lymphocytes express the Treg markers. Interleukin-10 is required for Treg induction by GILZ-expressing DCs. It is also needed for the suppressive function of Tregs. Antigen-presenting cells from patients treated with glucocorticoids generate interleukin-10-secreting Tregs ex vivo. These antigen-presenting cells produce GILZ, which is needed for Treg induction. Therefore, GILZ is critical for commitment of DCs to differentiate into regulatory DCs and to the generation of antigen-specific Tregs. This mechanism may contribute to the therapeutic effects of glucocorticoids.
Hamdi
Haifa
H
Institut National de la Santé et de la Recherche Médicale, Clamart, France.
Godot
Véronique
V
Maillot
Marie-Christine
MC
Prejean
Maria Victoria
MV
Cohen
Nicolas
N
Krzysiek
Roman
R
Lemoine
François M
FM
Zou
Weiping
W
Emilie
Dominique
D
D017951:Antigen Presentation / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects
D005938:Glucocorticoids; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D016753:Interleukin-10