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.

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

“…While some studies have followed injections of T cells, monocytes, or dendritic cells from the brain parenchyma to their ultimate drainage into the cervical lymph nodes, others have failed to document any such drainage after intracerebral injection (79,(86)(87)(88)(89). Furthermore, the perivascular pathway is likely incapable of allowing the passage of immune cells (48), raising the possibility that at least some of the observed drainage might be due to postinjection leakage into the CSF/meningeal compartment.…”

“…87, 88; and rostral migratory stream, ref. 86). In-depth analysis of the contribution and functions of the different paths under both normal and pathological conditions is necessary to fully understand how the immune system senses the CNS and how each route might differentially contribute to generating and maintaining immune responses toward the CNS.…”

Antigen Presentation After Stroke

“…A pathway for DCs to traffic via the rostral migratory stream from the brain to the cervical LN, where they present antigen to T cells for inducing immune tolerance was observed in a mouse model of MS [68]. The neuroprotective effect of these DC-mediated Tregs could be negatively affected by local sequestration induced by the immunomodulatory drug fingolimod [68].…”

“…A pathway for DCs to traffic via the rostral migratory stream from the brain to the cervical LN, where they present antigen to T cells for inducing immune tolerance was observed in a mouse model of MS [68]. The neuroprotective effect of these DC-mediated Tregs could be negatively affected by local sequestration induced by the immunomodulatory drug fingolimod [68]. Antigen can be processed and presented in a context that induces Tregs, which exert an immunomodulatory effect in response to antigen exposure and prevent activation of lymphocytes [69].…”

Roles of CD4 and CD8 T Lymphocytes in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

“…Although the brain and spinal cord do not have defined lymphatic channels as observed in most organs, there is still lymphatic drainage for the CSF and the interstitial fluid of the brain parenchyma to the cervical lymph nodes (Laman and Weller, 2013). Dendritic cells, which are professional APCs, can travel from the CNS via the rostral migratory stream to the cervical lymph nodes where peripheral T lymphocytes could be exposed to CNS antigens (Mohammad et al, 2014). Indeed, cervical lymph nodes obtained from patients with MS and animals (marmosets and mice) affected with EAE contain mature APCs that have engulfed myelin or neuronal antigens, supporting the notion that they can activate T lymphocytes (Laman and Weller, 2013).…”