Expression of CCR7 in multiple sclerosis: Implications for CNS immunity

Abstract

It is unclear how immune cells traffic between the lymphoid compartment and the central nervous system (CNS), which lacks lymphatic vessels and is shielded by the blood-brain barrier. We studied the expression of CCR7, a chemokine receptor required for migration of T cells and dendritic cells (DCs) to lymphoid organs, in the CNS of patients with multiple sclerosis (MS) to gain insight into pathways for CNS immune cell trafficking. Inflamed MS lesions contained numerous CCR7+ myeloid cells expressing major histocompatibility complex class II, CD68 and CD86, consistent with maturing DCs. CCR7+ DCs also were identified in cerebrospinal fluid (CSF). These observations suggested that the afferent limb of CNS immunity is comprised, in part, of DCs, which are generated within the CNS and migrate to deep cervical lymph nodes through the CSF after antigen capture. Ninety percent of CSF T cells expressed CCR7 and CSF from patients with MS was relatively depleted of CCR7-negative effector-memory T cells. In contrast, all T cells in parenchymal MS lesions lacked CCR7, indicating local retention and differentiation of central-memory T cells upon restimulation by antigen within the CNS. These data suggested that the efferent limb of CNS immunity is executed by central-memory T cells, which enter CSF directly from the circulation.

The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain

“…Our discovery that CCR7 ϩ CSF lymphoblasts have slightly increased Kv1.3 channels on their membrane, but are primed to rapidly become Kv1.3 high T EM has important implications in understanding CNS recruitment. These data are consistent with a recent report by another group (30) in which CSF cells were CCR7 ؉ but parenchymal cells were CCR7 Ϫ . We considered the possibility that CCR7 expression might reflect their activation state because we and others have reported that CCR7 is transiently up-regulated on T helper 1 cells during early activation (20,31).…”

Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis

“…Instead CCR7 predominantly stained parenchymal cells with a morphology resembling activated microglia in NLGM and NLWM (Fig. 1F, insert) as described previously for MS plaques (Kivisakk et al, 2004).…”

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

“…Since anti-inflammatory macrophages express the lymph node homing receptor CCR7 [50], we determined whether a CCR7-dependent mechanism could be involved. This study shows that, similar to APC in MS brain as well as MOG-containing cells in EAEaffected rhesus CLN [21,51], myelin-containing cells in human MS CLN and in vitro express CCR7, but MAP-2-containing cells do not. CLN from EAE-affected CCR7-deficient mice contain slightly more myelin and neuronal antigens as compared to CLN from EAE-affected wild-type mice, indicating that CCR7 is not necessarily involved.…”