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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    • "That is, upon activation with antigen (in the absence of the addition of any exogenous TGF-b), a population of regulatory T cells emerges from cells that have recognized antigen but show decreased mTOR activation. Previously, it has been showed that in the absence of exogenous TGF-b, stimulation with low doses of peptide can lead to the generation of increased Foxp3 þ T cells (Gottschalk et al. 2010). Indeed, we were able to recapitulate such findings and were further able to show that stimulation with low doses of peptide is associated with decreased mTOR activity. "
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    ABSTRACT: Current models of T-helper-cell differentiation depict the generation of effector cells from a naïve T cell based on the cytokine environment upon T-cell-receptor engagement. We propose a new model of CD4(+) T-cell activation, differentiation, and function whereby the outcome of antigen recognition is dictated by mTOR activity and the subsequent up-regulation of selective metabolic function. Such a model more readily explains the generation of effector and memory cells including the concept of effector and memory Foxp3(+) regulatory cells.
    Cold Spring Harbor Symposia on Quantitative Biology 10/2013; 78(1). DOI:10.1101/sqb.2013.78.020214
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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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