title: Loss of T regulatory cell suppression following signaling through glucocorticoid-induced tumor necrosis receptor (GITR) is dependent on c-Jun N-terminal kinase activation.
abstract: Naturally occurring Foxp3(+)CD4(+)CD25(+) T regulatory cell (nTreg)-mediated suppression of lung allergic responses is abrogated following ligation of glucocorticoid-induced tumor necrosis receptor (GITR) family-related protein. In vitro stimulation of nTregs with GITR ligand increased phosphorylation of c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated protein kinase (ERK) or p38 MAPK. SP600125, a known JNK inhibitor, prevented GITR-mediated phosphorylation of JNK. Activation of JNK was associated with increases in the upstream mitogen-activated protein kinase kinase 7 (MKK7) and the downstream transcription factor NF-κβ. Phosphorylated c-Jun (p-c-Jun), indicative of the activation of JNK, was detected in the immunoprecipitates of nTregs from wild-type but not JNK- or GITR-deficient mice. Treatment with an inhibitor of JNK phosphorylation resulted in complete reversal of all GITR-induced changes in nTreg phenotype and function, with full restoration of suppression of in vivo lung allergic responses and in vitro proliferation of activated CD4(+)CD25(-) T cells. Thus, regulation of JNK phosphorylation plays a central role in T regulatory cell function with therapeutic implications for the treatment of asthma and autoimmune diseases.
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206.
authors.forename: Anthony
authors.initials: A
authors.lastname: Joetham
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schedel
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206.
authors.forename: Joanne
authors.initials: J
authors.lastname: Domenico
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206.
authors.forename: Azzeddine
authors.initials: A
authors.lastname: Dakhama
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206. Electronic address: gelfande@njhealth.org.
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007108:Immune Tolerance / Q000187:drug effects / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000873:Anthracenes; D053450:Glucocorticoid-Induced TNFR-Related Protein; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C106544:Tnfrsf18 protein, mouse; C432165:pyrazolanthrone; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse