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CCR7 with S1P(1) signaling through AP-1 for migration of Foxp3(+) regulatory T-cells controls autoimmune exocrinopathy

Item Type:Article
Title:CCR7 with S1P(1) signaling through AP-1 for migration of Foxp3(+) regulatory T-cells controls autoimmune exocrinopathy
Creators Name:Ishimaru, N. and Yamada, A. and Nitta, T. and Arakaki, R. and Lipp, M. and Takahama, Y. and Hayashi, Y.
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.
Keywords:Autoimmune Diseases, Cell Movement, Chemotaxis, CCR7 Receptors, Exocrine Glands, Forkhead Transcription Factors, Inbred C57BL Mice, JNK Mitogen-Activated Protein Kinases, Lysophospholipids, MAP Kinase Signaling System, Regulatory T-Lymphocytes, Signal Transduction, Sphingosine, Transcription Factor AP-1, Animals, Mice
Source:American Journal of Pathology
ISSN:0002-9440
Publisher:Elsevier (U.S.A.)
Volume:180
Number:1
Page Range:199-208
Date:January 2012
Official Publication:https://doi.org/10.1016/j.ajpath.2011.09.027
PubMed:View item in PubMed

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