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      Mechanisms Underlying CD4+ Treg Immune Regulation in the Adult: From Experiments to Models

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          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.

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          Most cited references98

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          Regulatory T cell lineage specification by the forkhead transcription factor foxp3.

          Regulatory T cell-mediated dominant tolerance has been demonstrated to play an important role in the prevention of autoimmunity. Here, we present data arguing that the forkhead transcription factor Foxp3 acts as the regulatory T cell lineage specification factor and mediator of the genetic mechanism of dominant tolerance. We show that expression of Foxp3 is highly restricted to the subset alphabeta of T cells and, irrespective of CD25 expression, correlates with suppressor activity. Induction of Foxp3 expression in nonregulatory T cells does not occur during pathogen-driven immune responses, and Foxp3 deficiency does not impact the functional responses of nonregulatory T cells. Furthermore, T cell-specific ablation of Foxp3 is sufficient to induce the identical early onset lymphoproliferative syndrome observed in Foxp3-deficient mice. Analysis of Foxp3 expression during thymic development suggests that this mechanism is not hard-wired but is dependent on TCR/MHC ligand interactions.
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            A function for interleukin 2 in Foxp3-expressing regulatory T cells.

            Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.
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              Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.

              Despite accumulating evidence that regulatory T cells play a crucial role in preventing autoimmunity, the processes underlying their generation during immune repertoire formation are unknown. We show here that interactions with a single self-peptide can induce thymocytes that bear an autoreactive T cell receptor (TCR) to undergo selection to become CD4+CD25+ regulatory T cells. Selection of CD4+CD25+ thymocytes appears to require a TCR with high affinity for a self peptide because thymocytes that bear TCRs with low affinity do not undergo selection into this pathway. Our findings indicate that specificity for self-peptides directs the selection of CD4+CD25+ regulatory thymocytes by a process that is distinct from positive selection and deletion.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                23 September 2013
                18 November 2013
                2013
                : 4
                : 378
                Affiliations
                [1] 1Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa , Lisbon, Portugal
                [2] 2Instituto Gulbenkian de Ciência , Oeiras, Portugal
                [3] 3Theoretical Biology and Biophysics, Los Alamos National Laboratory , Los Alamos, NM, USA
                Author notes

                Edited by: Carmen Molina-Paris, University of Leeds, UK

                Reviewed by: Akihiko Yoshimura, Keio University, Japan; Fernando A. Arosa, University of Beira Interior, Portugal

                *Correspondence: Luis Graca, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028 Lisbon, Portugal e-mail: lgraca@ 123456fm.ul.pt ; Ruy M. Ribeiro, Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA e-mail: ruy@ 123456lanl.gov

                Present address: Ruy M. Ribeiro, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

                Luis Graca and Ruy M. Ribeiro are joint senior authors.

                This article was submitted to T Cell Biology, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2013.00378
                3831161
                24302924
                33edf6d6-48a6-4148-914f-9bea0fe8b7b6
                Copyright © 2013 Caridade, Graca and Ribeiro.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 August 2013
                : 03 November 2013
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 125, Pages: 9, Words: 7736
                Categories
                Immunology
                Mini Review

                Immunology
                tolerance,mathematical models,cd4-blockade,tregs,regulation
                Immunology
                tolerance, mathematical models, cd4-blockade, tregs, regulation

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