Liang S, Alard P, Zhao Y et al.Conversion of CD4+ CD25− cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med 201:127-137

Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, United States
Journal of Experimental Medicine (Impact Factor: 12.52). 02/2005; 201(1):127-37. DOI: 10.1084/jem.20041201
Source: PubMed


The CD4+ CD25+ regulatory T cells play a critical role in controlling autoimmunity, but little is known about their development and maintenance. In this study, we investigated whether CD4+ CD25- cells can convert to CD4+ CD25+ regulatory T cells in vivo under natural conditions. CD4+ CD25- cells from CD45.1+ mice were sorted and transferred into congenic CD45.2+ mice. Converted CD4+ CD25+ cells could be detected in lymphoid organs as early as 1 wk after transfer and by 6 wk after transfer, 5-12% of transferred CD4+ cells expressed CD25. Converted CD4+ CD25+ cells themselves failed to proliferate after stimulation, but could suppress proliferation of responder cells in vitro, and also expressed high levels of Foxp3 mRNA. In addition, CD4+ CD25- cells transferred into thymectomized congenic mice converted to CD4+ CD25+ cells that also suppressed responder cell proliferation in vitro, and expressed high levels of Foxp3 mRNA. Finally, CD4+ CD25- cells transferred into B7-/- mice failed to convert into CD4+ CD25+ cells that exhibit the regulatory phenotype. These data indicate that CD4+ CD25- cells convert into CD4+ CD25+ regulatory T cells spontaneously in vivo and suggest that this conversion process could contribute significantly to the maintenance of the peripheral CD4+ CD25+ regulatory T cell population.

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    • "All these observations about antigen specific tolerance mediating cells were made before natural CD4 + CD25 + Treg were de- scribed [204]. Conversion of CD4 + CD25 − T effector lineage cells to CD4 + CD25 + FOXP3 + T cells with regulatory function is established [77,205206207208209 and the critical role of naïve tTreg in tolerance induction appreciated , as elimination of these cells prevents tolerance induction. tTreg have hypomethylation of the TSDR for FOXP3 which stabilizes expression of FOXP3 and the Treg phenotype. "
    [Show abstract] [Hide abstract] 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
    • "Studies have reported that TGF-β has the ability to induce CD4 + CD25 − cells to become CD4 + CD25 + Tregs in vitro [52,53] , and TGF-β can induce FoxP3 expression in iTregs [54,55]. Additionally, other studies have clearly demonstrated that the suppressive capacity of FoxP3 + Tregs in vivo is via a TGF-β-dependent mechanism [56,57]. A number of studies indicate that decreased TGF-β serum and tissue levels are found in vitiligo patients, and this could have a deleterious effect upon Treg cell function in these individuals [58][59][60]. "
    [Show abstract] [Hide abstract] ABSTRACT: Vitiligo is a hypomelanotic autoimmune skin disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses against melanocytes. Regulatory T cells (Tregs) are crucial to the development of self-tolerance and so are major foci in the study of autoimmune pathogenesis of vitiligo. This review will summarise recent findings concerning the role of Tregs in the pathogenesis of vitiligo. In addition, as antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, new strategies that expand or induce de novo generation of Tregs and which are currently being investigated as therapies for other autoimmune diseases, will be discussed. These approaches will highlight the opportunities for Treg cell-based therapeutics in vitiligo.
    No preview · Article · Oct 2014 · Autoimmunity Reviews
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    • "In these conditions, homeostatic proliferation of the donor cells could be observed and part of the donor cell population became CD25+CTLA-4+GITR+Foxp3+ and acquired suppressive activity. Additionally, when congenitally marked CD4+ CD25− T cells were transferred to WT hosts, 10% of those converted into CD4+ CD25+ Foxp3+ T cells, within 6 weeks (52). "
    [Show abstract] [Hide abstract] ABSTRACT: To maintain immunological balance the organism has to be tolerant to self while remaining competent to mount an effective immune response against third-party antigens. An important mechanism of this immune regulation involves the action of regulatory T-cell (Tregs). In this mini-review, we discuss some of the known and proposed mechanisms by which Tregs exert their influence in the context of immune regulation, and the contribution of mathematical modeling for these mechanistic studies. These models explore the mechanisms of action of regulatory T cells, and include hypotheses of multiple signals, delivered through simultaneous antigen-presenting cell (APC) conjugation; interaction of feedback loops between APC, Tregs, and effector cells; or production of specific cytokines that act on effector cells. As the field matures, and competing models are winnowed out, it is likely that we will be able to quantify how tolerance-inducing strategies, such as CD4-blockade, affect T-cell dynamics and what mechanisms explain the observed behavior of T-cell based tolerance.
    Full-text · Article · Nov 2013 · Frontiers in Immunology
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