Glutamate Released by Dendritic Cells as a Novel Modulator of T Cell Activation

Pacheco, Rodrigo; Oliva, Harold; Martinez-Navío, José M.; Climent, Núria; Ciruela, Francisco; Gatell, José M.; Gallart, Teresa; Mallol, Josefa; Lluı́s, Carmen; Franco, Rafael

doi:10.4049/jimmunol.177.10.6695

Cited by 133 publications

(134 citation statements)

References 47 publications

(51 reference statements)

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“…Traditionally, it has been thought that the functions of immune cells such as T cells and DCs are regulated mainly by cytokines. However, a number of more recent studies have shown that immune system cells can also be regulated by neurotransmitters (6)(7)(8)(9)(10)(11). Consistent with this, both primary and secondary lymphoid organs are highly innervated by sympathetic ends that store dopamine (DA) (12,13).…”

Section: Endritic Cells (Dcs) Are the Most Efficient Type Of Apcsmentioning

confidence: 73%

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Prado

Contreras

González

et al. 2012

The Journal of Immunology

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110

129

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Dendritic cells (DCs) are responsible for priming T cells and for promoting their differentiation from naive T cells into appropriate effector cells. Emerging evidence suggests that neurotransmitters can modulate T cell-mediated immunity. However, the involvement of specific neurotransmitters or receptors remains poorly understood. In this study, we analyzed the role of dopamine in the regulation of DC function. We found that DCs express dopamine receptors as well as the machinery necessary to synthesize, store, and degrade dopamine. Notably, the expression of D5R decreased upon LPS-induced DC maturation. Deficiency of D5R on the surface of DCs impaired LPS-induced IL-23 and IL-12 production and consequently attenuated the activation and proliferation of Ag-specific CD4+ T cells. To determine the relevance of D5R expressed on DCs in vivo, we studied the role of this receptor in the modulation of a CD4+ T cell-driven autoimmunity model. Importantly, D5R-deficient DCs prophylactically transferred into wild-type recipients were able to reduce the severity of experimental autoimmune encephalomyelitis. Furthermore, mice transferred with D5R-deficient DCs displayed a significant reduction in the percentage of Th17 cells infiltrating the CNS without differences in the percentage of Th1 cells compared with animals transferred with wild-type DCs. Our findings demonstrate that by contributing to CD4+ T cell activation and differentiation to Th17 phenotype, D5R expressed on DCs is able to modulate the development of an autoimmune response in vivo.

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Section: Endritic Cells (Dcs) Are the Most Efficient Type Of Apcsmentioning

confidence: 73%

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Prado

Contreras

González

et al. 2012

The Journal of Immunology

Self Cite

110

129

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“…Bar, 10 m. C, ultrastructural characterization of human isolated islets exposed to elevated glutamate concentration. an inverted ␤-cell/␣-cell ratio and glucagon hypersecretion (30,42,43) and also during "insulitis" in T1DM islets because dendritic and T cells can release glutamate (44,45). Of note, changes in glutamate concentration in the islet have been reported in response to high glucose (46), and increased glutamate levels have been found in sera of subjects with both T1DM (47) and T2DM (48).…”

Section: Discussionmentioning

confidence: 98%

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

Cairano

Davalli

Perego

et al. 2011

Journal of Biological Chemistry

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Glutamate is the major excitatory neurotransmitter of the central nervous system (CNS) and may induce cytotoxicity through persistent activation of glutamate receptors and oxidative stress. Its extracellular concentration is maintained at physiological concentrations by high affinity glutamate transporters of the solute carrier 1 family (SLC1). Glutamate is also present in islet of Langerhans where it is secreted by the ␣-cells and acts as a signaling molecule to modulate hormone secretion. Whether glutamate plays a role in islet cell viability is presently unknown. We demonstrate that chronic exposure to glutamate exerts a cytotoxic effect in clonal ␤-cell lines and human islet ␤-cells but not in ␣-cells. In human islets, glutamate-induced ␤-cell cytotoxicity was associated with increased oxidative stress and led to apoptosis and autophagy. We also provide evidence that the key regulator of extracellular islet glutamate concentration is the glial glutamate transporter 1 (GLT1). GLT1 localizes to the plasma membrane of ␤-cells, modulates hormone secretion, and prevents glutamate-induced cytotoxicity as shown by the fact that its down-regulation induced ␤-cell death, whereas GLT1 up-regulation promoted ␤-cell survival. In conclusion, the present study identifies GLT1 as a new player in glutamate homeostasis and signaling in the islet of Langerhans and demonstrates that ␤-cells critically depend on its activity to control extracellular glutamate levels and cellular integrity.

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“…106 In addition, glutamate can augment the production of cytokines by lymphocytes, as well as their migratory ability. 107,108 GABA receptors appear to have an inhibitory function on immune responses in a subset of lymphocytes, 109 but may also increase pathogen clearance by macrophages. 110 Receptors for glutamate and GABA can act as targets for autoantibodies, resulting in symptoms associated with those often seen in ASD.…”

Section: Neurotransmittersmentioning

confidence: 99%

Immune Dysfunction in Autism: A Pathway to Treatment

2010

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Summary: Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians, schools, and service agencies worldwide have reported a dramatic increase in the number of children identified with autism. Despite expanding research, the etiology and underlying biological processes of autism remain poorly understood, and the relative contribution from genetic, epigenetic, and environmental factors remains unclear. Although autism affects primarily brain function (especially affect, social functioning, and cognition), it is unknown to what extent other organs and systems are disrupted. Published findings have identified widespread changes in the immune systems of children with autism, at both systemic and cellular levels. Brain specimens from autism subjects exhibit signs of active, ongoing inflammation, as well as alterations in gene pathways associated with immune signaling and immune function. Moreover, many genetic studies have indicated a link between autism and genes that are relevant to both the nervous system and the immune system. Alterations in these pathways can affect function in both systems. Together, these reports suggest that autism may in fact be a systemic disorder with connections to abnormal immune responses. Such immune system dysfunction may represent novel targets for treatment. A better understanding of the involvement of the immune response in autism, and of how early brain development is altered, may have important therapeutic implications.

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Glutamate Released by Dendritic Cells as a Novel Modulator of T Cell Activation

Cited by 133 publications

References 47 publications

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

The Glial Glutamate Transporter 1 (GLT1) Is Expressed by Pancreatic β-Cells and Prevents Glutamate-induced β-Cell Death

Immune Dysfunction in Autism: A Pathway to Treatment

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