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Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory T cell (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular ATP (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen-presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response., T cell activation triggers metabolic changes required to support the adaptive immune response (1-5). Indeed, the differentiation of cytotoxic and interleukin (IL)-17-producing effector T cells (T helper 17 cells; [T.sub.H]17 [...]

Regulatory T cells ([T.sub.reg]) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of [T.sub.reg] cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 ([T.sub.H]17). Although [T.sub.reg] cell dysfunction and/or TH17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of [T.sub.reg] and TH17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional [T.sub.reg] cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with [T.sub.reg] cell development, boosted [T.sub.H]17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both [T.sub.reg] and [T.sub.H]17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation., Pathogenic autoimmunity is controlled in healthy individuals by a specialized subset of T cells named [T.sub.reg] cells (1). [T.sub.reg] cell differentiation and function are driven by the transcription factor Foxp3 [...]

Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS). Thus, therapeutic approaches promoting neuroprotection could aid the treatment of progressive MS. Here, we used what we believe is a novel water-soluble fullerene derivative (ABS-75) attached to an NMDA receptor antagonist, which combines antioxidant and anti-excitotoxic properties, to block axonal damage and reduce disease progression in a chronic progressive EAE model. Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with myelin-oligodendrocyte glycoprotein (MOG). Reduced disease progression in ABS-75-treated mice was associated with reduced axonal loss and demyelination in the spinal cord. Fullerene ABS-75 halted oxidative injury, [CD11b.sup.+] infiltration, and CCL2 expression in the spinal cord of mice without interfering with antigen-specific T cell responses. In vitro, fullerene ABS-75 protected neurons from oxidative and glutamate-induced injury and restored glutamine synthetase and glutamate transporter expression in astrocytes under inflammatory insult. Glutamine synthetase expression was also increased in the white matter of fullerene ABS-75-treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases., Introduction Epidemiologic studies show that approximately 85% of patients with MS initially develop a relapsing-remitting form of the disease (1), (2). However, within 10 years, approximately half of those with [...]

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4[sup.+]CD25[sup.-]LAP[sup.+] regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-[beta]-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions., Author(s): Hirofumi Ochi [1, 3]; Michal Abraham [1, 3]; Hiroki Ishikawa [1]; Dan Frenkel [1]; Kaiyong Yang [1]; Alexandre S Basso [1]; Henry Wu [1]; Mei-Ling Chen [1]; Roopali Gandhi [...]

Beta2-adrenergic receptor ( B2 AR) signaling is known to impair Th1-cell differentiation and function in a c AMP-dependent way, leading to inhibition of cell proliferation and decreased production of IL-2 and IFN-γ. CD4+ Foxp3+ Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance. Nevertheless, very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function. Here we show that Foxp3+ Treg cells express functional B2 AR. B2 AR activation in Treg cells leads to increased intracellular c AMP levels and to protein kinase A ( PKA)-dependent CREB phosphorylation. We also found that signaling via B2 AR enhances the in vitro suppressive activity of Treg cells. B2 AR-mediated increase in Treg-cell suppressive function was associated with decreased IL-2 m RNA levels in responder CD4+ T cells and improved Treg-cell-induced conversion of CD4+ Foxp3− cells into Foxp3+ induced Treg cells. Moreover, B2 AR signaling increased CTLA-4 expression in Treg cells in a PKA-dependent way. Finally, we found that PKA inhibition totally prevented the B2 AR-mediated increase in Treg-cell suppressive function. Our data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through B2 AR signaling. [ABSTRACT FROM AUTHOR]

Background: Mice allergic to ovalbumin (OVA) avoid drinking a solution containing this antigen. This was interpreted as related to IgE-dependent mast cell degranulation and sensory C fiber activation. Methods: We employed pharmacological manipulation to further investigate the mediators involved in immune-induced food aversion. Results: While nonimmunized rats preferred a sweetened OVA solution, immunized rats avoided it. We also employed a paradigm in which rats are conditioned to drink water for two 10-min sessions a day. Tolerant rats presented lower IgE titers, and this manipulation abrogated food aversion. Dexamethasone (1.0 mg/kg) prevented the aversion of OVA-immunized rats to the antigen-containing solution. Combined blockade of H1 and 5-hydroxytryptamine (5-HT)2 receptors by promethazine (3.0 mg/kg) plus methysergide (5.0 mg/kg) was unable to alter food aversion. Blockade of 5-HT3 receptors by ondansetron (1.0 mg/kg) caused a twofold increase in the ingestion of the sweetened OVA solution by immunized rats, suggesting the involvement of 5-HT3 receptors in food aversion. Finally, we showed that dexamethasone or promethazine plus methysergide, but not ondansetron, effectively prevented the IgE-dependent mast-cell-degranulation-induced increase in vascular permeability in rats. Conclusion: We suggest that regardless of whether or not they cause edema, IgE-mediated mast cell degranulation and consequent 5-HT3 signaling are involved in the process that triggers avoidance to the source of the allergen in allergic rats. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of Treg cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (TH17). Although Treg cell dysfunction and/or TH17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of Treg and TH17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional Treg cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with Treg cell development, boosted TH17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both Treg and TH17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation. [ABSTRACT FROM AUTHOR]

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+CD25−LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-β–dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions. [ABSTRACT FROM AUTHOR]

The authors reflect on lymphocytes, which are considered vital in fighting infections as they display powerful effectormechanisms. They mention the function and products of lymphocytes, ranging from the neutralization of pathogens with specific antibodies to the activation of macrophages and to direct cytotoxic activity. They provide information about lymphocyte progenitors.

Despite accumulating evidence indicating that neurotransmitters released by the sympathetic nervous system can modulate the activity of innate immune cells, we still know very little about how norepinephrine impacts signaling pathways in dendritic cells (DC) and the consequence of that in DC-driven T cell differentiation. In this article, we demonstrate that p2-adrenergic receptor ((β2AR) activation in LPS-stimulated DC does not impair their ability to promote T cell proliferation; however, it diminishes IL- 12p70 secretion, leading to a shift in the IL-12p70/IL-23 ratio. Although (CAR stimulation in DC induces protein kinase Adependent cAMP-responsive element-binding protein phosphorylation, the effect of changing the profile of cytokines produced upon LPS challenge occurs in a protein kinase A-independent manner and, rather, is associated with inhibition of the NF-κB and AP-1 signaling pathways. Moreover, as a consequence of the inverted IL-12p70/IL-23 ratiofollowing (CAR stimulation, LPSstimulated DC promoted the generation of CD4+ T cells that, upon TCR engagement, produced lower amounts of IFN-y and higher levels of IL-17. These findings provide new insights into molecular and cellular mechanisms by which (CAR stimulation in murine DC can influence the generation of adaptive immune responses and may explain some aspects of how sympathetic nervous system activity can modulate immune function. [ABSTRACT FROM AUTHOR]

Beta2-adrenergic receptor (B2AR) signaling is known to impair Th1-cell differentiation and function in a cAMP-dependent way, leading to inhibition of cell proliferation and decreased production of IL-2 and IFN-γ. CD4(+) Foxp3(+) Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self-tolerance. Nevertheless, very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function. Here we show that Foxp3(+) Treg cells express functional B2AR. B2AR activation in Treg cells leads to increased intracellular cAMP levels and to protein kinase A (PKA)-dependent CREB phosphorylation. We also found that signaling via B2AR enhances the in vitro suppressive activity of Treg cells. B2AR-mediated increase in Treg-cell suppressive function was associated with decreased IL-2 mRNA levels in responder CD4(+) T cells and improved Treg-cell-induced conversion of CD4(+) Foxp3(-) cells into Foxp3(+) induced Treg cells. Moreover, B2AR signaling increased CTLA-4 expression in Treg cells in a PKA-dependent way. Finally, we found that PKA inhibition totally prevented the B2AR-mediated increase in Treg-cell suppressive function. Our data suggest that sympathetic fibers are able to regulate Treg-cell suppressive activity in a positive manner through B2AR signaling., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)