title: JNK2 regulates the functional plasticity of naturally occurring T regulatory cells and the enhancement of lung allergic responses.
abstract: Glucocorticoid-induced TNFR family-related protein (GITR)-mediated activation of JNK was shown to regulate the suppressive activity of CD4(+)CD25(+) naturally occurring T regulatory cells (nTregs) in wild-type (WT) hosts. In this study, CD4(+)CD25(+) T cells were shown to be capable of becoming pathogenic effector cells in sensitized and challenged CD8(-/-) recipient mice. Only GITR-expressing CD4(+)CD25(+) T cells, but neither GITR knocked-in CD4(+)CD25(-) T cells nor GITR-silenced CD4(+)CD25(+) T cells, enhanced development of lung allergic responses. Inhibition of JNK in WT nTregs or nTregs from GITR(-/-)and JNK2(-/-) mice failed to enhance lung allergic responses in sensitized and challenged CD8(-/-) recipient mice. The failure to enhance responses was associated with increased bronchoalveolar lavage fluid levels of IL-10 and TGF-β and decreased levels of IL-5, IL-6, and IL-13. In contrast, nTregs from JNK1(-/-) mice, similar to WT nTregs, were fully effective in enhancing responses. Thus, GITR stimulation of nTregs and signaling through JNK2, but not JNK1, triggered the loss of regulatory function while concomitantly gaining pathogenic CD4(+) T effector cell function responsible for exacerbating asthma-like immunopathology.
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206.
authors: Anthony
authors: A
authors: Joetham
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206.
authors: Michaela
authors: M
authors: Schedel
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206.
authors: Katsuyuki
authors: K
authors: Takeda
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206.
authors: Yi
authors: Y
authors: Jia
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206.
authors: Shigeru
authors: S
authors: Ashino
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206.
authors: Azzeddine
authors: A
authors: Dakhama
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206.
authors: Anna
authors: A
authors: Lluis
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206.
authors: Masakazu
authors: M
authors: Okamoto
authors: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206 gelfande@njhealth.org.
authors: Erwin W
authors: EW
authors: Gelfand
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000276:immunology; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; C556062:IL10 protein, mouse; C106544:Tnfrsf18 protein, mouse; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8