Immune cell trafficking from the brain maintains CNS immune tolerance

Mohammad G. Mohammad, Vicky W. W. Tsai, Marc Ruitenberg, Masoud Hassanpour, Hui Li, Prudence Hart, Samuel N. Breit, Paul E. Sawchenko, David A. Brownl

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fmgolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fmgolimod treatment might exacerbate CNS neuroinflarnmation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.

Original languageEnglish
Pages (from-to)1228-1241
Number of pages14
JournalThe Journal of clinical investigation
Volume124
Issue number3
Early online date24 Feb 2014
DOIs
Publication statusPublished - 3 Mar 2014

Cite this

Mohammad, M. G., Tsai, V. W. W., Ruitenberg, M., Hassanpour, M., Li, H., Hart, P., Breit, S. N., Sawchenko, P. E., & Brownl, D. A. (2014). Immune cell trafficking from the brain maintains CNS immune tolerance. The Journal of clinical investigation, 124(3), 1228-1241. https://doi.org/10.1172/JCI71544