title: CCR7 with S1P1 signaling through AP-1 for migration of Foxp3+ regulatory T-cells controls autoimmune exocrinopathy.
abstract: Forkhead box p3-positive (Foxp3(+)) regulatory T cells (T(reg) cells) participate in maintaining peripheral immune tolerance and suppressing autoimmunity. We recently reported that in situ patrolling by C-C-chemokine receptor 7 (CCR7)(+) T(reg) cells in target organs is essential for controlling autoimmune lesions in Sjögren's syndrome. In the present study, the molecular mechanism underlying CCR7-mediated T(reg) cell migration was investigated in a mouse model. The impaired migratory response of Ccr7(-/-) T(reg) cells to sphingosine 1-phosphate (S1P) occurred because of defective association of S1P receptor 1 (S1P(1)) with a G coupled-protein. In addition, T-cell receptor (TCR)- and S1P(1)-mediated Ras-related C3 botulinum toxin substrate 1 (Rac-1), extracellular signal-related kinase (ERK), and c-Jun phosphorylation required for activator protein 1 (AP-1) transcriptional activity were significantly impaired in Ccr7(-/-) T(reg) cells. Surprisingly, the abnormal nuclear localization of Foxp3 was detected after abrogation of the c-Jun and Foxp3 interaction in the nucleus of Ccr7(-/-) T(reg) cells. These results indicate that CCR7 essentially controls the migratory function of T(reg) cells through S1P(1)-mediated AP-1 signaling, which is regulated through its interaction with Foxp3 in the nucleus.
authors: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. ishimaru@dent.tokusghima-u.ac.jp
authors: Naozumi
authors: N
authors: Ishimaru
authors: Akiko
authors: A
authors: Yamada
authors: Takeshi
authors: T
authors: Nitta
authors: Rieko
authors: R
authors: Arakaki
authors: Martin
authors: M
authors: Lipp
authors: Yousuke
authors: Y
authors: Takahama
authors: Yoshio
authors: Y
authors: Hayashi
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000503:physiopathology*; D002465:Cell Movement / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology; D005088:Exocrine Glands / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008246:Lysophospholipids / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D054400:Receptors, CCR7 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*
chemical_list: C515371:Ccr7 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008246:Lysophospholipids; D054400:Receptors, CCR7; D018808:Transcription Factor AP-1; C060506:sphingosine 1-phosphate; D048031:JNK Mitogen-Activated Protein Kinases; D013110:Sphingosine