title: Regulation of experimental autoimmune encephalomyelitis by TPL-2 kinase.
abstract: Tumor progression locus 2 (TPL-2) expression is required for efficient polarization of naive T cells to Th1 effector cells in vitro, as well as for Th1-mediated immune responses. In the present study, we investigated the potential role of TPL-2 in Th17 cells. TPL-2 was found to be dispensable for Th17 cell differentiation in vitro, and for the initial priming of Th17 cells in experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated disease model for multiple sclerosis. Nevertheless, TPL-2-deficient mice were protected from EAE, which correlated with reduced immune cell infiltration, demyelination, and axonal damage in the CNS. Adoptive transfer experiments demonstrated that there was no T cell-intrinsic function for TPL-2 in EAE, and that TPL-2 signaling was not required in radiation-sensitive hematopoietic cells. Rather, TPL-2 signaling in radiation-resistant stromal cells promoted the effector phase of the disease. Importantly, using a newly generated mouse strain expressing a kinase-inactive form of TPL-2, we demonstrated that stimulation of EAE was dependent on the catalytic activity of TPL-2 and not its adaptor function to stabilize the associated ubiquitin-binding protein ABIN-2. Our data therefore raise the possibility that small molecule inhibitors of TPL-2 may be beneficial in multiple sclerosis therapy.
authors.affiliation: Divisions of Immune Cell Biology, National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: Srividya
authors.initials: S
authors.lastname: Sriskantharajah
authors.affiliation: Divisions of Immune Cell Biology, National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Gückel
authors.affiliation: Institute for Immunology, Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Attica, Greece.
authors.forename: Niki
authors.initials: N
authors.lastname: Tsakiri
authors.affiliation: Department of Neuropathology & BIOSS Center for Biological Signaling, University of Freiburg, D-79106 Freiburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kierdorf
authors.affiliation: Divisions of Immune Cell Biology, National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Brender
authors.affiliation: Divisions of Immune Cell Biology, National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: Abduelhakem
authors.initials: A
authors.lastname: Ben-Addi
authors.affiliation: Molecular Immunology, National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Veldhoen
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.affiliation: Molecular Immunology, National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Stockinger
authors.affiliation: Immunoregulation, National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
authors.affiliation: Department of Neuropathology & BIOSS Center for Biological Signaling, University of Freiburg, D-79106 Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Institute for Immunology, Biomedical Sciences Research Center 'Alexander Fleming', 16672 Vari, Attica, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.affiliation: Divisions of Immune Cell Biology, National Institute for Medical Research, London, NW7 1AA, UK.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D008213:Lymphocyte Activation / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000009:adverse effects; D010446:Peptide Fragments / Q000009:adverse effects; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55); D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse