Regular article
Immunopathology and infectious disease
CCR7 with S1P1 Signaling through AP-1 for Migration of Foxp3+ Regulatory T-Cells Controls Autoimmune Exocrinopathy

https://doi.org/10.1016/j.ajpath.2011.09.027Get rights and content
Under an Elsevier user license
open archive

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.

Cited by (0)

Supported by Funding Program for Next Generation World-Leading Researchers in Japan (LS090), Grants-in-Aid for Scientific Research (no. 17109016 and 17689049) from the Ministry of Education, Science, Sport, and Culture of Japan, and by funds from the Uehara Memorial Foundation and the Takeda Science Foundation (N.I.).

Supplemental material for this article can be found at http://ajp.amjpathol.org or at doi: 10.1016/j.ajpath.2011.09.027.