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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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Cell Proliferation
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Chronic Disease
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / immunology
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Energy Metabolism / genetics
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Energy Metabolism / immunology*
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Female
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Glycoproteins / immunology
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Glycoproteins / metabolism
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Humans
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism
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Leptin / genetics
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Leptin / immunology*
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Leptin / metabolism
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Mice
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Mice, Obese
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / immunology
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Mitogen-Activated Protein Kinase 3 / metabolism
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Multiple Sclerosis / genetics
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Multiple Sclerosis / immunology*
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Multiple Sclerosis / metabolism
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Multiple Sclerosis / pathology
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments / immunology
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Peptide Fragments / metabolism
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Phosphorylation / genetics
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Phosphorylation / immunology
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / immunology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Species Specificity
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / immunology*
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TOR Serine-Threonine Kinases / metabolism
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Th1 Cells / immunology*
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Th1 Cells / metabolism
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Th1 Cells / pathology
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Th17 Cells / immunology*
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Th17 Cells / metabolism
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Th17 Cells / pathology
Substances
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Cdkn1b protein, mouse
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Glycoproteins
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Leptin
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Proto-Oncogene Proteins c-bcl-2
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myelin oligodendrocyte glycoprotein (35-55)
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Cyclin-Dependent Kinase Inhibitor p27
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 3