Immune cell trafficking from the brain maintains CNS immune tolerance
Mohammad G. Mohammad, Vicky W.W. Tsai, Marc J. Ruitenberg, Masoud Hassanpour, Hui Li, Prue H. Hart, Samuel N. Breit, Paul E. Sawchenko, David A. Brown
Mohammad G. Mohammad, Vicky W.W. Tsai, Marc J. Ruitenberg, Masoud Hassanpour, Hui Li, Prue H. Hart, Samuel N. Breit, Paul E. Sawchenko, David A. Brown
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Research Article

Immune cell trafficking from the brain maintains CNS immune tolerance

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 fingolimod 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 fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.

Authors

Mohammad G. Mohammad, Vicky W.W. Tsai, Marc J. Ruitenberg, Masoud Hassanpour, Hui Li, Prue H. Hart, Samuel N. Breit, Paul E. Sawchenko, David A. Brown

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Figure 4

Leukocytes migrate from the CNS to CxLNs.

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Leukocytes migrate from the CNS to CxLNs. In icv-cannulated mice, after ...
In icv-cannulated mice, after 7 days of CFSE infusion, CxLN CD45+ cells were gated and examined for CFSE labeling. (A) CFSE-labeled cells were discerned in all mice. The percentage of CFSE+ cells is indicated. (B) The same experiment repeated with fingolimod or vehicle administered i.p. (n = 6; 3 independent experiments), beginning 1 day prior to icv cannula implantation. For gating of CFSE+ CxLN and ILN monocytes, see Supplemental Figure 4. Top: Vehicle-treated mice (large arrow) had substantial populations of CFSE+ presumed macrophages (CD45+CD3–B220–CD11c–CD11b+), which were significantly reduced in CxLNs from fingolimod-treated mice (small arrow) and absent in ILNs of either vehicle- or drug- treated mice. Bottom: CFSE+ DCs (CD45+CD3–CD11c+) were only seen in CxLNs of vehicle-treated mice (arrow), and their accumulation was completely inhibited by systemic fingolimod treatment. (C) Mice that had CFSE infused by icv cannula had their brains removed, and mononuclear cells were extracted for FACS. Top: DC and macrophage/PMN accumulation in the brains of cannulated mice. Bottom: To determine which cell type(s) may have accumulated as a result of injury associated with icv cannulation, we also administered fingolimod (6 μg/d) or vehicle (n = 6; 3 independent experiments) i.p. to noncannulated mice, which demonstrated an increased frequency of DCs in the CNS as assessed by FACS (P = 0.018), with no differences in corresponding macrophage/PMN or T cell numbers. Data represent mean ± SEM. *P < 0.05.