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* Department of Biochemistry and Molecular Biology, Faculty of Biology and Institut d’Investigació Biomèdica August Pi i Sunyer, University of Barcelona, Barcelona, Spain;
Service of Immunology, Hospital Clínic de Barcelona, Barcelona, Spain;
AIDS Research Group of Institut d’Investigació Biomèdica August Pi i Sunyer, Faculty of Medicine, University of Barcelona, Barcelona, Spain; and
Service of Infectious Diseases and AIDS Unit, Hospital Clínic de Barcelona, Barcelona, Spain
Adaptive immune responses begin after productive immunosynaptic contacts formation established in secondary lymphoid organs by dendritic cells (DC) presenting the Ag to T lymphocytes. Despite its resemblance to the neurosynapse, the participation of soluble small nonpeptidic mediators in the intercellular cross-talk taking place during T cell–DC interactions remains poorly studied. In this study, we show that human DC undergoing maturation and in contact with T cells release significant amounts of glutamate, which is the main excitatory neurotransmitter in mammalians. The release of glutamate is nonvesicular and mediated by the DC-expressed Xc– cystine/glutamate antiporter. DC-derived glutamate stimulating the constitutively expressed metabotropic glutamate receptor 5 impairs T cell activation. However, after productive Ag presentation, metabotropic glutamate receptor 1 is expressed in T cells to mediate enhanced T cell proliferation and secretion of Th1 and proinflammatory cytokines. These data suggest that, during T cell–DC interaction, glutamate is a novel and highly effective regulator in the initiation of T cell-mediated immune responses.
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1 This work was supported by the Fundació Marató of Catalonian Telethon (Grant 02/021010 to R.F.); the Directorate of Research of the Catalan Government (Grant SGR 2000/00093 to R.F.); the Ministerio de Sanidad (FIS03-1200 to T.G.); the Ministerio de Educación y Ciencia (Grant SAF 2005-05566 to J.M.G.); and the Foundation for the Investigation and Prevention of AIDS in Spain (Grant FIPSE 36536-05 to T.G.). F.C. currently holds a Ramón y Cajal research contract signed with the Ministerio de Ciencia y Tecnología.
2 H.O. and J.M.M.-N. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Rafael Franco, Department of Biochemistry and Molecular Biology, Faculty of Biology and Institut D’investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Diagonal 645, Barcelona E-08028, Spain. E-mail address: rfranco{at}ub.edu
4 Abbreviations used in this paper: iGluR, ionotropic glutamate receptor; mGluR, metabotropic GluR; AAA, 
-aminoadipic acid; ADA, adenosine deaminase; CPCCOEt, 7-(hydroxyimino)cyclopropan-chromen-1a-carboxylate ethylester; DC, dendritic cell, iDC, immature DC; mDC, mature DC; MPEP, 6-methyl-2-(phenylethynyl)-pyridine; pAb, polyclonal antibody; SATg, extract of soluble Ags from Toxoplasma gondii; SEA, staphylococcal enterotoxin A; Var, attenuated varicella vaccine; 
2m, 2-microglobulin.
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