Adaptive Islet-Specific Regulatory CD4 T Cells Control Autoimmune Diabetes and Mediate the Disappearance of Pathogenic Th1 Cells In Vivo

Department of Immunology, Sidney Kimmel Cancer Center, San Diego, CA 92131, USA.
The Journal of Immunology (Impact Factor: 4.92). 05/2006; 176(8):4730-9. DOI: 10.4049/jimmunol.176.8.4730
Source: PubMed


Adaptive regulatory T cells that develop from naive CD4 cells in response to exposure to Ag can act as immunotherapeutic agents to control immune responses. We show that effectors generated from murine islet-specific CD4 cells by TCR stimulation with IL-2 and TGF-beta1 have potent suppressive activity. They prevent spontaneous development of type 1 diabetes in NOD mice and inhibit development of pancreatic infiltrates and disease onset orchestrated by Th1 effectors. These regulatory T cells do not require innate CD25+ regulatory cells for generation or function, nor do they share some characteristics typically associated with them, including expression of CD25. However, the adaptive population does acquire the X-linked forkhead/winged helix transcription factor, FoxP3, which is associated with regulatory T cell function and maintains expression in vivo. One mechanism by which they may inhibit Th1 cells is via FasL-dependent cytotoxicity, which occurs in vitro. In vivo, they eliminate Th1 cells in lymphoid tissues, where Fas/FasL interactions potentially play a role because Th1 cells persist when this pathway is blocked. The results suggest that adaptive regulatory CD4 cells may control diabetes in part by impairing the survival of islet-specific Th1 cells, and thereby inhibiting the localization and response of autoaggressive T cells in the pancreatic islets.

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Available from: Linda Bradley, Dec 05, 2014
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    • "In these studies, we demonstrated that the adoptive transfer of antigen specific TGFβ induced Tregs were effective at stopping the progression of disease in TxA23 mice at the later stages of AIG (Figure 2). Although iTregs have been demonstrated to be effective at preventing various diseases in mouse models of human disease when given prior to or very shortly after disease induction [10], [14], [15], [41]–[43], few have examined the ability of iTregs to suppress autoimmunity at the late stage of disease. At the time of treatment, 4-months of age, TxA23 have developed pathological changes and molecular biomarkers seen in humans with chronic gastric inflammation. "
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    ABSTRACT: Strategies to boost the numbers and functions of regulatory T cells (Tregs) are currently being tested as means to treat autoimmunity. While Tregs have been shown to be effective in this role, strategies to manipulate Tregs to effectively suppress later stages of ongoing diseases need to be established. In this study, we evaluated the ability of TGF-β-induced Tregs (iTregs) specific for the major self-antigen in autoimmune gastritis to suppress established autoimmune gastritis in mice. When transferred into mice during later stages of disease, iTregs demethylated the Foxp3 promoter, maintained Foxp3 expression, and suppressed effector T cell proliferation. More importantly, these iTregs were effective at stopping disease progression. Untreated mice had high numbers of endogenous Tregs (enTregs) but these were unable to stop disease progression. In contrast, iTregs, were found in relatively low numbers in treated mice, yet were effective at stopping disease progression, suggesting qualitative differences in suppressor functions. We identified several inhibitory receptors (LAG-3, PD-1, GARP, and TNFR2), cytokines (TGF-β1 and IL12p35), and transcription factors (IRF4 and Tbet) expressed at higher levels by iTregs compared to enTregs isolated form mice with ongoing disease, which likely accounts for superior suppressor ability in this disease model. These data support efforts to use iTregs in therapies to treat establish autoimmunity, and show that iTregs are more effective than enTregs at suppressing inflammation in this disease model.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Naive Treg cells might be activated in the periphery by self-antigen and subsequently converted to mTreg cells in T1D mice or patients [28], [29]. The mTreg cells induced in vitro were capable of persisting as effector memory cells after transfer and were protective against the development of T1D [28], [30]. Several studies have reported the existence of a small population of Tregs and also mTreg cells in the peripheral blood of healthy adult individuals and preferentially activated Tm cells in diabetic patients [4], [29]. "
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    ABSTRACT: Vaccination could induce immune tolerance and protected NOD mice from the development of type I diabetes (T1D). We previously demonstrated that insulin peptide (B9-23) combined with dexamethasone (DEX) stimulated the expansion of antigen specific regulatory T (Treg) cells which in turn effectively prevented T1D in NOD mice. Here, we aimed to investigate the therapeutic effect of tolerogenic vaccination for T1D treatment. The diabetic NOD mice (Blood glucose level ≧250 mg/dl) were treated with B9-23 and DEX twice. The tolerance was restored by blocking maturation of dendritic cells (DCs) and inducing Treg cells in treated NOD mice. Remarkably, the reduction of autoreactive effector memory CD4 T (Tm) cells and the induction of functional effector memory Treg (mTreg) cells contributed to the improvement of T1D in treated NOD mice. Tolerogenic vaccination restored tolerance and ameliorated T1D by suppressing effector CD4 Tm cells and inducing effector mTreg cells. Our findings implicate the potential of tolerogenic vaccination for T1D treatment.
    Preview · Article · Jul 2013 · PLoS ONE
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    • "The ability of iTreg cells to be generated in large numbers makes them an attractive alternative for the treatment of human autoimmune disorders unresponsive to current approaches (Trzonkowski et al., 2009; Brunstein et al., 2011; Di Ianni et al., 2011; Hippen et al., 2011a). In vitro-derived iTreg cells are functionally suppressive in animal models of inflammatory bowel disease (Fantini et al., 2006), diabetes (Weber et al., 2006), autoimmune gastritis (DiPaolo et al., 2007), experimental autoimmune encephalitis (Selvaraj and Geiger, 2008), and Foxp3-deficiency (Huter et al., 2008). Notably, in vitro-derived iTreg cells contribute to tolerance in disease models where in vivo-derived iTreg cells are absent (Haribhai et al., 2009, 2011). "
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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.
    Full-text · Article · Jun 2013 · Frontiers in Immunology
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