Rapamycin Promotes Expansion of Functional CD4+CD25+FOXP3+ Regulatory T Cells of Both Healthy Subjects and Type 1 Diabetic Patients

University of Salzburg, Salzburg, Salzburg, Austria
The Journal of Immunology (Impact Factor: 4.92). 01/2007; 177(12):8338-47. DOI: 10.4049/jimmunol.177.12.8338
Source: PubMed


CD4+CD25+FOXP3+ T regulatory cells (Tregs) are pivotal for the induction and maintenance of peripheral tolerance in both mice and humans. Rapamycin has been shown to promote tolerance in experimental models and to favor CD4+CD25+ Treg-dependent suppression. We recently reported that rapamycin allows in vitro expansion of murine CD4+CD25+FoxP3+ Tregs, which preserve their suppressive function. In the current study, we show that activation of human CD4+ T cells from healthy subjects in the presence of rapamycin leads to growth of CD4+CD25+FOXP3+ Tregs and to selective depletion of CD4+CD25- T effector cells, which are highly sensitive to the antiproliferative effect of the compound. The rapamycin-expanded Tregs suppress proliferation of both syngeneic and allogeneic CD4+ and CD8+ T cells. Interestingly, rapamycin promotes expansion of functional CD4+CD25+FOXP3+ Tregs also in type 1 diabetic patients, in whom a defect in freshly isolated CD4+CD25+ Tregs has been reported. The capacity of rapamycin to allow growth of functional CD4+CD25+FOXP3+ Tregs, but also to deplete T effector cells, can be exploited for the design of novel and safe in vitro protocols for cellular immunotherapy in T cell-mediated diseases.

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Available from: Manuela Battaglia, Jan 09, 2016
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    • "Stimulator cells include dendritic cells [63] [93], irradiated PBMC [84] [94] [95], B cells [20] [96] or CD40L activated B cells [97]. Addition of rapamycin that spares Treg activation but blocks effector cells [98] [99] [100] [101] enhances activated antigen specific Treg expansion [102]. The majority of studies culture and restimulate repeatedly for between 12 and 40 days. "
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    ABSTRACT: CD4(+)CD25(+)FOXP3(+)T regulatory cells (Treg) play a major role in prevention of induction and control of immune responses, and contribute to induction of immune tolerance. Natural or thymic Treg (tTreg) have non-antigen specific suppressor action. Tolerance to a specific antigen is also mediated by CD4(+)CD25(+)FOXP3(+)Treg, but the source of these cells is disputed. Many suggest that they are derived from effector lineage CD4(+)CD25(-)FOXP3(-)T cells and are induced Treg (iTreg). Our work shows that tTreg with specific TCR for the antigen can be activated to more potent antigen specific Treg. We have demonstrated that initial activation of tTreg with antigen and IL-2 induces antigen specific Treg that express receptors for the late Th1 cytokines IFN-γ and IL-12. These antigen specific Treg suppress effector lineage T cells at much lower ratios than tTreg, and we call these Ts1 cells as they are activated by Th1 cytokines and express receptors for Th1 cytokines. Further activation of Ts1 cells with specific antigen and late Th1 cytokines such as IL-12 induces very potent Th1-like Treg, that express t-bet, the transcription factor for Th1 cells, as well as the Th1 cytokine IFN-γ. Similar Th1-like Treg can be induced in IL-2 activated tTreg, by IFN-γ or IL-27. tTreg activated by antigen in the presence of IL-4 induces antigen specific Treg that express the IL-5 receptor, and these Ts2 cells can be induced to Th2-like Treg by IL-5 and antigen. tTreg can be activated to antigen specific Tregs that induce tolerance and have therapeutic potential. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Apr 2015 · International immunopharmacology
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    • "Therefore, certain cytokines and chemicals need to be determined to enable the expansion of functional Treg cells, which will not secrete pro-inflammatory cytokines. Rapamycin (also known as Sirolimus/Rapamune) likely be useful as a component as it substantially increases the purity of Treg cells by eliminating non-Treg cells (71). "
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    ABSTRACT: Regulatory T (Treg) cells are essential for normal immune surveillance systems, and their dysfunction leads to development of diseases, such as autoimmune disorders. CD4(+)CD25(+) Treg cells are well-known suppressive cells, which express the transcription factor Foxp3, are indispensable for the maintenance of immune self-tolerance and homeostasis by suppressing aberrant or excessive immune response. Other Foxp3(-) Treg cells include Tr1, Th3, CD8(+)CD28(-/-), and Qa1-restricted T cells; however, the contribution of these Treg cells to self-tolerance, immune homeostasis as well as preventing autoimmunity is not well defined. Here, we discuss the phenotypes and function of Foxp3(+) Treg cells and the potential use of such Treg cells against rheumatoid arthritis (RA). Of note, even though most expanded populations of Foxp3(+) Treg cells exhibit suppressive activity, tissue-associated or antigen-specific Treg cells appear superior in suppressing local autoimmune disorders such as RA. In addition, utilizing tissue-associated Foxp3(+) Treg cells from stem cells may stable Foxp3 expression and avoid induction of a potentially detrimental systemic immunosuppression.
    Full-text · Article · Aug 2014 · Frontiers in Oncology
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    • "Rapamycin is an inhibitor of mTOR pathway, which is able to favor the proliferation of Treg cells [31]. Here we conclude that iTreg induced from naïve T cells would acquire an enhanced CD25 and FoxP3 expression in the presence of rapamycin. "
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    ABSTRACT: It has been shown that rapamycin is able to significantly increase the expression of FoxP3 and suppress activity in induced Treg (iTreg) cells in vivo and in vitro. CD39 is a newly determined Treg marker that relates to cell suppression. Runx1, a regulator of FoxP3, controls the expression of adenosine deaminase (ADA) gene, which is found recently in the downstream of CD39 pathway in trophoblast cells. Whether rapamycin would influence CD39 pathway and regulate the expression of Runx1 remains to be determined. The addition of rapamycin to human CD4+ naïve cells in the presence of IL-2, TGF-β promotes the expression of FoxP3. In this paper, we found that CD39 positively correlated with the FoxP3 expression in iTreg cells. Rapamycin induced iTreg cells showed a stronger CD39/Runx1 expression with the enhanced suppressive function. These data suggested that CD39 expression was involved in iTreg generation and the enhanced suppressive ability of rapamycin induced Treg was partly due to Runx1 pathway. We conclude that rapamycin favors CD39/Runx1 expression in human iTreg and provides a novel insight into the mechanisms of iTreg generation enhanced by rapamycin.
    Full-text · Article · Mar 2014 · Journal of Immunology Research
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