Induction of antigen-specific regulatory T lymphocytes by human dendritic cells expressing the glucocorticoid-induced leucine zipper

Abstract

IntroductionRegulatory T lymphocytes (Tregs) play a key role in controlling immune responses. Initially, 2 types of Tregs were identified. Natural (or constitutive) Tregs are generated in the thymus and they spontaneously express the transcription factor FOXP3 and high levels of CD25. Inducible (or adaptive) Tregs are generated by peripheral activation, particularly in the presence of IL-10 or TGF␤. However, the relationship between these 2 subpopulations has not been completely elucidated. Tregs inhibit immune responses by a combination of effects requiring direct contact with their targets and the production of inhibitory cytokines, including IL-10 and TGF␤. In addition to the coexpression of CD25 hi and FOXP3 and the production of IL-10 and TGF␤, several markers potentially characteristic of Tregs have been identified, but none of them has been unequivocally associated with the suppressive function of Tregs or with their classification into natural or inducible Tregs. [1][2][3][4] Antigen presentation by dendritic cells (DCs) leads to either immune stimulation or tolerance. The mechanisms underlying the decision of DCs to orientate the immune response toward one of these 2 opposite outcomes are not fully understood. Toleranceinducing DCs are also called regulatory DCs. One method used by regulatory DCs to prevent immune activation is to trigger T-lymphocyte anergy or apoptosis during antigen presentation. This involves production of the enzyme indoleamine 2,3-dioxygenase (IDO) and of nitric oxide by DCs. 5,6 The other method is to generate regulatory cells, including Tregs. Although IDO production by DCs may play a role in the induction of Tregs, 7 additional mechanisms are presumably involved. The state of maturation and activation of DCs is critical to Treg development: DCs activated and maturing in response to inflammatory stimuli trigger immune responses, but immature or "semimature" DCs, in contrast, induce tolerance, [8][9][10][11] and this is in part mediated by the generation of Tregs. [12][13][14][15] Phenotypically mature DCs can also be tolerogenic, and certain environmental signals can induce maturation of DCs in a tolerogenic mode. 10 IL-10, TGF␤, glucocorticoids (GCs), vasoactive intestinal peptide, vitamin D3, and antioxidative vitamins, used alone or in combination, orientate DC maturation to induce tolerance, [16][17][18][19][20][21][22][23][24] and Treg development has been demonstrated for several of these agents. 18,19,22,24 The molecular mechanisms involved in this switch of DC maturation toward regulatory DCs are largely unknown. Several tolerogenic agents down-regulate the NF-kB and p38 MAPK transduction pathways in DCs, which contrasts with the potency of inflammatory agents to activate them. 24,25 In addition, DCs from RelB-deficient mice induce immune tolerance and antigen-specific Tregs. 26 This suggests that modulation of NF-kB and p38 MAPK function contributes to the decision of DCs to differentiate into regulatory DCs.An intracellular factor called glucocorticoid-induced leucine ...

Hepatocyte Growth Factor Limits Autoimmune Neuroinflammation via Glucocorticoid-Induced Leucine Zipper Expression in Dendritic Cells

“…A common trait of tolerogenic DCs generated by IL-10, GCs, and TGF-b1 is the expression of GILZ (25). Expression of the GILZ molecule by DCs allows the induction of Treg cells and prevents DCs from activating Ag-specific T cells (22,25). In this study, we show that HGF has a strong stimulatory effect on GILZ expression in DCs.…”

Les protéines de la famille TSC-22D

“…En effet, GILZ augmente l'expression des molécules B7-H1/CD274 et ILT3/CD85k, ainsi que la production d'IL-10 -une cytokine immunosuppressive -dans les cellules dendritiques humaines [19]. Le phénotype de ces cellules dendritiques surexprimant GILZ leur permet d'orienter la différenciation des lymphocytes T CD4 + spécifiques de l'antigène en lymphocytes T régulateurs, caractérisés par l'expression du facteur FOXP3 (forkhead box P3) et de CD25, et par la production d'IL-10 [35] (Figure 3). À l'appui de ces observations, une plus faible expression de GILZ a été mesurée dans les cellules dendritiques de patients souffrant d'allergies respiratoires, et la restauration par GILZ conduit à une induction de la différenciation des lymphocytes T en lymphocytes T régulateurs, caractérisés par l'expression de FOXP3 et de CD25 [35].…”

“…Le phénotype de ces cellules dendritiques surexprimant GILZ leur permet d'orienter la différenciation des lymphocytes T CD4 + spécifiques de l'antigène en lymphocytes T régulateurs, caractérisés par l'expression du facteur FOXP3 (forkhead box P3) et de CD25, et par la production d'IL-10 [35] (Figure 3). À l'appui de ces observations, une plus faible expression de GILZ a été mesurée dans les cellules dendritiques de patients souffrant d'allergies respiratoires, et la restauration par GILZ conduit à une induction de la différenciation des lymphocytes T en lymphocytes T régulateurs, caractérisés par l'expression de FOXP3 et de CD25 [35]. GILZ inhibe également l'expression des molécules de surface CD80 et CD86, et des chimiokines MIP1 et RANTES, par les monocytes/macrophages [19,21].…”

Role of caspase-8 in thymus function

“…Because of the variety of protein interactions and its abundance in several cell types, GILZ has, in fact, a crucial role in controlling protein trafficking and signaling. Most recently, novel functions have been defined, including regulation of T helper cell differentiation 72,73 and DC function, 74,75 increase of epithelial Na þ channel-mediated Na þ transport in the kidney, 76,77 and control of malignant transformation through inhibition of Ras-driven tumorigenesis. 71,78,79 Young adult GILZ-overexpressing transgenic mice exhibit dramatically reduced numbers of CD4 þ CD8 þ thymocytes and increased ex vivo thymocyte apoptosis.…”