Regular articleImmunopathology and infectious diseaseCCR7 with S1P1 Signaling through AP-1 for Migration of Foxp3+ Regulatory T-Cells Controls Autoimmune Exocrinopathy

Forkhead box p3-positive (Foxp3+) regulatory T cells (Treg cells) participate in maintaining peripheral immune tolerance and suppressing autoimmunity. We recently reported that in situ patrolling by C-C-chemokine receptor 7 (CCR7)+ Treg cells in target organs is essential for controlling autoimmune lesions in Sjögren's syndrome. In the present study, the molecular mechanism underlying CCR7-mediated Treg cell migration was investigated in a mouse model. The impaired migratory response of Ccr7−/− Treg cells to sphingosine 1-phosphate (S1P) occurred because of defective association of S1P receptor 1 (S1P1) with a G coupled-protein. In addition, T-cell receptor (TCR)- and S1P1-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−/− Treg cells. Surprisingly, the abnormal nuclear localization of Foxp3 was detected after abrogation of the c-Jun and Foxp3 interaction in the nucleus of Ccr7−/− Treg cells. These results indicate that CCR7 essentially controls the migratory function of Treg cells through S1P1-mediated AP-1 signaling, which is regulated through its interaction with Foxp3 in the nucleus.