TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo

Department of Immunology, Howard Hughes Medical Institute, New York, NY 10021, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/2010; 207(8):1701-11. DOI: 10.1084/jem.20091999
Source: PubMed


T cell receptor (TCR) ligation is required for the extrathymic differentiation of forkhead box p3(+) (Foxp3(+)) regulatory T cells. Several lines of evidence indicate that weak TCR stimulation favors induction of Foxp3 in the periphery; however, it remains to be determined how TCR ligand potency influences this process. We characterized the density and affinity of TCR ligand favorable for Foxp3 induction and found that a low dose of a strong agonist resulted in maximal induction of Foxp3 in vivo. Initial Foxp3 induction by weak agonist peptide could be enhanced by disruption of TCR-peptide major histocompatibility complex (pMHC) interactions or alteration of peptide dose. However, time course experiments revealed that Foxp3-positive cells induced by weak agonist stimulation are deleted, along with their Foxp3-negative counterparts, whereas Foxp3-positive cells induced by low doses of the strong agonist persist. Our results suggest that, together, pMHC ligand potency, density, and duration of TCR interactions define a cumulative quantity of TCR stimulation that determines initial peripheral Foxp3 induction. However, in the persistence of induced Foxp3(+) T cells, TCR ligand potency and density are noninterchangeable factors that influence the route to peripheral tolerance.

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    • "IL-10 has a profound effect on T cells as well. For example, reduced IL-12 production by DC affected by IL-10 antagonizes the development of T helper type 1 (Th1) responses while reduced MHC II levels on DC result in presentation of low density antigen that preferentially stimulates differentiation of regulatory CD4 T cells (7, 8). IL-10 can also act directly on T cells to inhibit synthesis of cytokines like IL-2 and IFNγ in CD4 T cells or to inhibit their proliferation (3). "
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    ABSTRACT: Dendritic cells (DC) in the spleen are highly activated following intravenous vaccination with a foreign-antigen, promoting expansion of effector T cells, but remain phenotypically and functionally immature after vaccination with a self-antigen. Up-regulation or suppression of expression of a cohort of pancreatic enzymes 24-72 h post-vaccination can be used as a biomarker of stimulatory versus tolerogenic DC, respectively. Here we show, using MUC1 transgenic mice and a vaccine based on the MUC1 peptide, which these mice perceive as a self-antigen, that the difference in enzyme expression that predicts whether DC will promote immune response or immune tolerance is seen as early as 4-8 h following vaccination. We also identify early production of IL-10 as a predominant factor that both correlates with this early-time point and controls DC function. Pre-treating mice with an antibody against the IL-10 receptor prior to vaccination results in DC that up-regulate CD40, CD80, and CD86 and promote stronger IFNγ+ T cell responses. This study suggests that transient inhibition of IL-10 prior to vaccination could improve responses to cancer vaccines that utilize self-tumor antigens.
    Frontiers in Immunology 02/2014; 5:59. DOI:10.3389/fimmu.2014.00059
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    • "Therefore, it is possible that TCR stimulation was insufficient to induce Foxp3 in adoptive transferred Foxp3− CD4+ T cells from wild-type polyclonal mice in these reports. Peripheral induction of Foxp3 appears to favor suboptimal TCR stimulation (Kretschmer et al., 2005; Gottschalk et al., 2010), however, TCR stimulation is required for induction of Foxp3 (Ohkura et al., 2012). Therefore, we cannot discount the possibility that the Induced Foxp3+ T-regs are regulated by DCs in vivo. "
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    ABSTRACT: Dendritic cells (DCs) are specialized antigen-presenting cells that regulate both immunity and tolerance. DCs in the periphery play a key role in expanding naturally occurring Foxp3(+) CD25(+) CD4(+) regulatory T cells (Natural T-regs) and inducing Foxp3 expression (Induced T-regs) in Foxp3(-) CD4(+) T cells. DCs are phenotypically and functionally heterogeneous, and further classified into several subsets depending on distinct marker expression and their location. Recent findings indicate the presence of specialized DC subsets that act to expand Natural T-regs or induce Foxp3(+) T-regs from Foxp3(-) CD4(+) T cells. For example, two major subsets of DCs in lymphoid organs act differentially in inducing Foxp3(+) T-regs from Foxp3(-) cells or expanding Natural T-regs with model-antigen delivery by anti-DC subset monoclonal antibodies in vivo. Furthermore, DCs expressing CD103 in the intestine induce Foxp3(+) T-regs from Foxp3(-) CD4(+) T cells with endogenous TGF-β and retinoic acid. In addition, antigen-presenting DCs have a capacity to generate Foxp3(+) T-regs in the oral cavity where many antigens and commensals exist, similar to intestine and skin. In skin and skin-draining lymph nodes, at least six DC subsets have been identified, suggesting a complex DC-T-reg network. Here, we will review the specific activity of DCs in expanding Natural T-regs and inducing Foxp3(+) T-regs from Foxp3(-) precursors, and further discuss the critical function of DCs in maintaining tolerance at various locations including skin and oral cavity.
    Frontiers in Immunology 06/2013; 4:151. DOI:10.3389/fimmu.2013.00151
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    • "Specific TCR affinity and TCR-derived signals, costimulatory molecules, and cytokines promote optimal in vivo iTreg cell development. Low doses of high affinity ligands promote iTreg cell generation by creating a decreased aggregate TCR stimulation as compared to Tconv cells (Kretschmer et al., 2005; Gottschalk et al., 2010). Strong CD28 costimulation (Semple et al., 2011) and CTLA-4 blockade (Zheng et al., 2006) are detrimental to de novo induction of Foxp3 whereas activation of Tconv cells under conditions of suboptimal costimulation promotes the induction of Foxp3. "
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    ABSTRACT: CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells are essential to the balance between pro- and anti-inflammatory responses. There are two major subsets of Treg cells, "natural" Treg (nTreg) cells that develop in the thymus, and "induced" Treg (iTreg) cells that arise in the periphery from CD4(+) Foxp3(-) conventional T cells and can be generated in vitro. Previous work has established that both subsets are required for immunological tolerance. Additionally, in vitro-derived iTreg cells can reestablish tolerance in situations where Treg cells are decreased or defective. This review will focus on iTreg cells, drawing comparisons to nTreg cells when possible. We discuss the molecular mechanisms of iTreg cell induction, both in vivo and in vitro, review the Foxp3-dependent and -independent transcriptional landscape of iTreg cells, and examine the proposed suppressive mechanisms utilized by each Treg cell subset. We also compare the T cell receptor repertoire of the Treg cell subsets, discuss inflammatory conditions where iTreg cells are generated or have been used for treatment, and address the issue of iTreg cell stability.
    Frontiers in Immunology 06/2013; 4:152. DOI:10.3389/fimmu.2013.00152
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