NorthWest Biotherapeutics Inc (NWBO)

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DC TRAFFICKING FROM THE CNS TO DRAINING LYMPH NODES

Immune surveillance of the CNS not only depends on migration of immune-competent cells into the CNS, it also requires drainage or trafficking of CNS-derived antigens to secondary lymphoid organs, more specifically to the cervical lymph nodes. In mice, exogenous antigens injected intracerebrally (134) or intracerebroventricularly (135) are capable of eliciting humoral and cellular immune responses in the cervical lymph nodes, providing evidence for an intact afferent immunity in the immune-privileged CNS. Nevertheless, Hatterer et al found that DC injected into the brain parenchyma of healthy rats demonstrate limited migration capacity and could not be detected in the cervical lymph nodes, whereas DC injected into the CSF did migrate to the cervical lymph nodes (136). However, others demonstrated that antigen-loaded bone marrow-derived DC injected intracerebrally into the CNS of naïve mice are capable of reaching the cervical lymph nodes, where they subsequently induce antigen-specific T-cell responses (137). Treatment of DC with pertussis toxin prior to intracerebral injection prevented their migration to the cervical lymph nodes, suggesting that an active, most likely chemokine receptor-driven pathway is responsible for this process, rather than passive drainage (137).

Although still rather controversial, 3 different routes for DC migration out of the CNS have been reported to date. Hochmeister et al demonstrated that bone marrow-derived DC injected into the striatum of rats migrate to the perivascular space, where they interact with the BBB endothelium and subsequently enter the blood vessel lumen (138). A second route was identified by Mohammad et al (2), as they described a CXCL12-CXCR4-dependent pathway for DC migration associated with the rostral migratory stream, which connects the olfactory bulb to the periventricular regions. Interestingly, interfering with DC migration along this rostral migratory stream pathway by targeted fingolimod treatment during EAE was shown to break immune tolerance and to increase EAE severity (2). A third exit route from the CNS comprises drainage via the CSF and the recently identified dural lymphatic vessels (139, 140). Indeed, CD11c+ cells with a DC-like morphology have been identified in the lumen of these meningeal lymphatic vessels (139). Migration along this route is probably coordinated in large part by the chemokines CCL19 (96, 128) and CCL21 (139) and their receptor CCR7 (127). In support of this hypothesis, Clarkson et al showed that Ccr7+/+ but not Ccr7-/- myelin-loaded DC reached the cervical lymph nodes after intracerebral injection into the CNS of EAE mice (141), or after recruitment to the inflamed CNS of mice inflicted with EAE (142).

. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901086/