How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes

Abstract

The lack of draining lymphatic vessels in the central nervous system (CNS) contributes to the so-called "CNS immune privilege." However, despite such a unique anatomic feature, dendritic cells (DCs) are able to migrate from the CNS to cervical lymph nodes through a yet unknown pathway. In this report, labeled bone marrow-derived myeloid DCs were injected stereotaxically into the cerebrospinal fluid (CSF) or brain parenchyma of normal rats. We found that DCs injected within brain parenchyma migrate little from their site of injection and do not reach cervical lymph nodes. In contrast, intra-CSFinjected DCs either reach cervical lymph nodes or, for a minority of them, infiltrate the subventricular zone, where neural stem cells reside. Surprisingly, DCs that reach cervical lymph nodes preferentially IntroductionUnder normal conditions, the transport of immune cells from blood to the central nervous system (CNS) is restricted by 2 physical barriers: the blood-brain barrier formed by CNS parenchymal microvessels and the blood cerebrospinal fluid (CSF) barrier formed by the choroid plexuses. Also, the circulation of immune cells from brain to lymphoid organs is hampered by the lack of CNS-draining lymphatic vessels. Nevertheless, immune responses may develop in the CNS, and cervical lymph nodes are considered as major sites of antigen presentation during neuroinflammatory diseases. 1,2 Indeed, antigens are drained from the CNS to cervical lymph nodes along the axons of craniofacial peripheral nerves. 3,4 Also, it was reported that dendritic cells (DCs) are able to migrate out of the CNS and, in turn, to elicit a CNS-targeted immune response. 5,6 However, it is not clear whether DCs circulating out of the CNS actually migrate from brain parenchyma or from the CSF compartment. This point is of importance because DCs are absent from normal CNS parenchyma, 7 but they can be detected in CSF and in compartments associated with CSF circulation or production, including meninges and choroid plexuses. [8][9][10] Moreover, under neuroinflammatory conditions, DCs accumulate in the CSF 11,12 as well as in perivascular spaces, 13,14 anatomic compartments draining into the CSF. These findings, along with others, suggest that the CSF may be a major transport route for DCs circulating in the CNS and migrating either from CSF to CNS parenchyma or from CSF to the lymphoid organs. 11,12,15,16 In the present study, we tracked bone marrow-derived myeloid DCs injected stereotaxically into the CSF or brain parenchyma of rats under normal conditions. Materials and methods AnimalsAnimal care and procedures were conducted according to the guidelines approved by the French Ethical Committee (decree 87-848) and the European Community directive 86-609-EEC and meet the Neuroscience Society guidelines. The study protocol was approved by the ethical committee of Faculté de Médecine Laennec, Lyon, France. Eight-to 10-week-old female Sprague Dawley rats were obtained from Harlan (Gannat, France). ReagentsMurine GM-CSF, human Flt3-L, murine IL-4, and h...

High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation

“…However, this is not the case when antigens or virus particles are delivered by intrathecal immunization Harling-Berg et al, 1991;Panda et al, 1965;Stevenson et al, 1997;Shin et al, 2006). It is likely that after IC inoculation of the CDV, virus induced leakage of neural cells and redirected viral antigens to the cerebrospinal fluid, the meninges and finally to the cervical lymph nodes (Hatterer et al, 2006).…”

Antigen Presentation After Stroke

“…Thus, APCs would capture neural antigens in the lymph nodes. Alternatively, APCs could take up antigen in the brain and then travel to the lymph nodes [34]. Expectedly, the presence of immature DCs presenting brain antigens in the lymph nodes would induce tolerance by causing anergy of T lymphocytes or by expanding regulatory T cells (Tregs) [35].…”

Brain-Derived Antigens in Lymphoid Tissue of Patients with Acute Stroke

“…In addition, molecules can reach the CLN by bulk flow of the intracranial fluids (11,12). Indeed, brain-derived Ags or APCs carrying these Ags can reach the CLN under experimental conditions, (13)(14)(15)(16) and the presence of brain-derived Ags in the CLN is recognized in human anatomic studies (17,18) and in sporadic clinical descriptions (13,19,20) of patients with multiple sclerosis.…”