title: Leptin modulates the survival of autoreactive CD4+ T cells through the nutrient/energy-sensing mammalian target of rapamycin signaling pathway.
abstract: Chronic inflammation can associate with autoreactive immune responses, including CD4(+) T cell responses to self-Ags. In this paper, we show that the adipocyte-derived proinflammatory hormone leptin can affect the survival and proliferation of autoreactive CD4(+) T cells in experimental autoimmune encephalomyelitis, an animal model of human multiple sclerosis. We found that myelin olygodendrocyte glycoprotein peptide 35-55 (MOG(35-55))-specific CD4(+) T cells from C57BL/6J wild-type mice could not transfer experimental autoimmune encephalomyelitis into leptin-deficient ob/ob mice. Such a finding was associated with a reduced proliferation of the transferred MOG(35-55)-reactive CD4(+) T cells, which had a reduced degradation of the cyclin-dependent kinase inhibitor p27(kip1) and ERK1/2 phosphorylation. The transferred cells displayed reduced Th1/Th17 responses and reduced delayed-type hypersensitivity. Moreover, MOG(35-55)-reactive CD4(+) T cells in ob/ob mice underwent apoptosis that associated with a downmodulation of Bcl-2. Similar results were observed in transgenic AND-TCR- mice carrying a TCR specific for the pigeon cytochrome c 88-104 peptide. These molecular events reveal a reduced activity of the nutrient/energy-sensing AKT/mammalian target of rapamycin pathway, which can be restored in vivo by exogenous leptin replacement. These results may help to explain a link between chronic inflammation and autoimmune T cell reactivity.
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Galgani
authors.forename: Claudio
authors.initials: C
authors.lastname: Procaccini
authors.forename: Veronica
authors.initials: V
authors.lastname: De Rosa
authors.forename: Fortunata
authors.initials: F
authors.lastname: Carbone
authors.forename: Paolo
authors.initials: P
authors.lastname: Chieffi
authors.forename: Antonio
authors.initials: A
authors.lastname: La Cava
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matarese
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002908:Chronic Disease; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013045:Species Specificity; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: C493961:Cdkn1b protein, mouse; D006023:Glycoproteins; D020738:Leptin; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C445081:myelin oligodendrocyte glycoprotein (35-55); D050760:Cyclin-Dependent Kinase Inhibitor p27; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048052:Mitogen-Activated Protein Kinase 3