Dendritic cells (DCs) competent to express the regulatory enzyme IDO in mice are a small but distinctive subset of DCs. Previously, we reported that a high-dose systemic CpG treatment to ligate TLR9 ...in vivo induced functional IDO exclusively in splenic CD19(+) DCs, which stimulated resting Foxp3-lineage regulatory T cells (Tregs) to rapidly acquire potent suppressor activity. In this paper, we show that IDO was induced in spleen and peripheral lymph nodes after CpG treatment in a dose-dependent manner. Induced IDO suppressed local T cell responses to exogenous Ags and inhibited proinflammatory cytokine expression in response to TLR9 ligation. IDO induction did not occur in T cell-deficient mice or in mice with defective B7 or programmed death (PD)-1 costimulatory pathways. Consistent with these findings, CTLA4 or PD-1/PD-ligand costimulatory blockade abrogated IDO induction and prevented Treg activation via IDO following high-dose CpG treatment. Consequently, CD4(+)CD25(+) T cells uniformly expressed IL-17 shortly after TLR9 ligation. These data support the hypothesis that constitutive interactions from activated T cells or Tregs and IDO-competent DCs via concomitant CTLA4→B7 and PD-1→PD-ligand signals maintain the default potential to regulate T cell responsiveness via IDO. Acute disruption of these nonredundant interactions abrogated regulation via IDO, providing novel perspectives on the proinflammatory effects of costimulatory blockade therapies. Moreover, interactions between IDO-competent DCs and activated T cells in lymphoid tissues may attenuate proinflammatory responses to adjuvants such as TLR ligands.
Following CD80/86 (B7) and TLR9 ligation, small subsets of splenic dendritic cells expressing CD19 (CD19+ DC) acquire potent T cell regulatory functions due to induced expression of the intracellular ...enzyme indoleamine 2,3‐dioxygenase (IDO), which catabolizes tryptophan. In CD19+ DC, IFN type I (IFN‐α) is the obligate inducer of IDO. We now report that IFN‐α production needed to stimulate high‐level expression of IDO following B7 ligation is itself dependent on basal levels of IDO activity. Genetic and pharmacologic ablation of IDO completely abrogated IFN‐α production by CD19+ DC after B7 ligation. In contrast, IDO ablation did not block IFN‐α production by CD19+ DC after TLR9 ligation. IDO‐mediated control of IFN‐α production depended on tryptophan depletion as adding excess tryptophan also blocked IFN‐α expression after B7 ligation. Consistent with this, DC from mice deficient in general control of non‐derepressible‐2 (GCN2)‐kinase, a component of the cellular stress response to amino acid withdrawal, did not produce IFN‐α following B7 ligation, but produced IFN‐α after TLR9 ligation. Thus, B7 and TLR9 ligands stimulate IFN‐α expression in CD19+ DC via distinct signaling pathways. In the case of B7 ligation, IDO activates cell‐autonomous signals essential for IFN‐α production, most likely by activating the GCN2‐kinase‐dependent stress response.
See accompanying commentary: http://dx.doi.org/10.1002/eji.20073737184
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
CpG oligodeoxynucleotides (CpG-ODNs) stimulate innate and adaptive immunity by binding to TLR9 molecules. Paradoxically, expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is ...induced following i.v. CpG-ODN administration to mice. CpG-ODNs induced selective IDO expression by a minor population of splenic CD19+ dendritic cells (DCs) that did not express the plasmacytoid DC marker 120G8. Following CpG-ODN treatment, CD19+ DCs acquired potent IDO-dependent T cell suppressive functions. Signaling through IFN type I receptors was essential for IDO up-regulation, and CpG-ODNs induced selective activation of STAT-1 in CD19+ DCs. Thus, CpG-ODNs delivered systemically at relatively high doses elicited potent T cell regulatory responses by acting on a discrete, minor population of splenic DCs. The ability of CpG-ODNs to induce both stimulatory and regulatory responses offers novel opportunities for using them as immunomodulatory reagents but may complicate therapeutic use of CpG-ODNs to stimulate antitumor immunity in cancer patients.
Nanoparticles containing DNA complexed with the cationic polymer polyethylenimine are efficient vehicles to transduce DNA into cells and organisms. DNA/polyethylenimine nanoparticles (DNPs) also ...elicit rapid and systemic release of proinflammatory cytokines that promote antitumor immunity. In this study, we report that DNPs possess previously unrecognized immunomodulatory attributes due to rapid upregulation of IDO enzyme activity in lymphoid tissues of mice. IDO induction in response to DNP treatment caused dendritic cells and regulatory T cells (Tregs) to acquire potent regulatory phenotypes. As expected, DNP treatment stimulated rapid increase in serum levels of IFN type I (IFN-αβ) and II (IFN-γ), which are both potent IDO inducers. IDO-mediated Treg activation was dependent on IFN type I receptor signaling, whereas IFN-γ receptor signaling was not essential for this response. Moreover, systemic IFN-γ release was caused by TLR9-dependent activation of NK cells, whereas TLR9 signaling was not required for IFN-αβ release. Accordingly, DNPs lacking immunostimulatory TLR9 ligands in DNA stimulated IFN-αβ production, induced IDO, and promoted regulatory outcomes, but did not stimulate potentially toxic, systemic release of IFN-γ. DNP treatment to induce IDO and activate Tregs blocked Ag-specific T cell responses elicited in vivo following immunization and suppressed joint pathology in a model of immune-mediated arthritis. Thus, DNPs lacking TLR9 ligands may be safe and effective reagents to protect healthy tissues from immune-mediated destruction in clinical hyperimmune syndromes.
By ligating CD80/CD86 (B7) molecules, the synthetic immunomodulatory reagent CTLA4-Ig (soluble synthetic CTLA4 fusion protein) induces expression of the enzyme indoleamine 2,3-dioxygenase (IDO) in ...some dendritic cells (DCs), which acquire potent T cell regulatory functions as a consequence. Here we show that this response occurred exclusively in a population of splenic DCs co-expressing the marker CD19. B7 ligation induced activation of the transcription factor signal transducer and activator of transcription (STAT1) in sorted CD19+, but not CD19NEG, DCs. STAT1 activation occurred even when DCs lacked receptors for type II IFN (IFNγ); however, STAT1 activation and IDO up-regulation were not observed when DCs lacked receptors for type I IFN (IFNαβ). Thus, IFNα, but not IFNγ, signaling was essential for STAT1 activation and IDO up-regulation in CD19+ DCs following B7 ligation. Consistent with these findings, B7 ligation also induced sorted CD19+, but not CD19NEG, DCs to express IFNα. Moreover, recombinant IFNα induced CD19+, but not CD19NEG, DCs to mediate IDO-dependent T cell suppression, showing that IFNα signaling could substitute for upstream signals from B7. These data reveal that a minor population of splenic DCs expressing the CD19 marker is uniquely responsive to B7 ligation, and that IFNα-mediated STAT1 activation is an essential intermediary signaling pathway that promotes IDO induction in these DCs. Thus, CD19+ DCs may be a target for regulatory T cells expressing surface CTLA4, and may suppress T cell responses via induction of IDO.
A discrete population of splenocytes with attributes of dendritic cells (DCs) and coexpressing the B-cell marker CD19 is uniquely competent to express the T-cell regulatory enzyme indoleamine ...2,3-dioxygenase (IDO) in mice treated with TLR9 ligands (CpGs). Here we show that IDO-competent cells express the B-lineage commitment factor Pax5 and surface immunoglobulins. CD19 ablation abrogated IDO-dependent T-cell suppression by DCs, even though cells with phenotypic attributes matching IDO-competent cells developed normally and expressed IDO in response to interferon γ. Consequently, DCs and regulatory T cells (Tregs) did not acquire T-cell regulatory functions after TLR9 ligation, providing an alternative perspective on the known T-cell regulatory defects of CD19-deficient mice. DCs from B-cell-deficient mice expressed IDO and mediated T-cell suppression after TLR9 ligation, indicating that B-cell attributes were not essential for B-lymphoid IDO-competent cells to regulate T cells. Thus, IDO-competent cells constitute a distinctive B-lymphoid cell type with quintessential T-cell regulatory attributes and phenotypic features of both B cells and DCs.
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Scurfy mice develop CD4 T-cell–mediated lymphoproliferative disease leading to death within 4 weeks of age. The scurfy mutation causes loss of function of the foxp3 gene (foxp3sf), which is essential ...for development and maintenance of naturally occurring regulatory CD4 T cells (nTregs). In humans, mutations of the foxp3 gene cause immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX). In most patients with IPEX and also in scurfy mice, T cells show hyperreactivity and levels of Th1- and Th2-associated cytokines are substantially elevated. We report that removal of CD28 expression rescued scurfy mice from early death. Longer-term surviving CD28-deficient scurfy mice still had lymphoproliferative disorder, but their CD4 T cells showed decreased interferon-γ and no sign of interleukin-4 or interleukin-10 hyperproduction. Furthermore, injection of CTLA4-Ig to block CD28-B7 interactions substantially improved the survival of scurfy mice by blocking effector T-cell differentiation. These data support the hypothesis that CD28-B7 interactions play a critical role in the etiology of lethal autoimmune disease in scurfy mice by stimulating the differentiation of antigen-activated naive T cells into effector T cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Optimal MAV operations in an uncertain environment Pachter, Meir; Chandler, Phillip R.; Darbha, Swaroop
International journal of robust and nonlinear control,
01/2008, Volume:
18, Issue:
2
Journal Article
Peer reviewed
In this paper, we consider a problem of sequential resource allocation. Such a problem arises in a simplified intelligence, surveillance and reconnaissance scenario where a micro air vehicle (MAV) is ...tasked with classification in an environment with false, that is, clutter, targets. The MAV visits the objects of interest in a specified sequence. A human operator is tasked with aiding the MAV's automatic target recognition system with the classification of objects, based on the images sent to him from the MAVs. If the images do not resolve the ambiguity concerning the status of the object being classified, the operator may request that the object be revisited. In this paper, for the sake of exposition of the employed methods and clarity of presentation, we assume that every object may be revisited at most once. Each object can be revisited and re‐examined in L⩾ 1 ways. There is an information gain whose value is given by the running reward. The information gain depends on the way an object is re‐examined, and the feedback from the operator but it is the same for all the objects. There is a random operator delay in communicating his findings to the MAV and the probability density function of the delay is assumed known. The MAV has a limited fuel reserve and upon getting feedback from the operator (and hence, knowing the delay associated with the object of interest only and not with those that it must revisit in the future), it must decide whether to revisit the object and if so, which of the L ways is optimal so as to maximize the total expected reward. In every revisit, fuel is expended from the reserve and is proportional to twice the delay plus a fixed cost, which is dependent on the way in which the object is re‐examined. We employ a stochastic dynamic programming approach to solve this problem. Specifically, for the case when L = 1, we show that there is an optimal threshold for each object and it is optimal to revisit the object if the delay is at most the threshold and not to revisit otherwise. For the case when L > 1, the structure of the optimal decision algorithm is not as simple, but it can be computed off‐line so as to facilitate its real‐time implementation. Published in 2007 by John Wiley & Sons, Ltd.
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