The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells

Abstract

Trafficking of antigen-presenting cells into the CNS is essential for lymphocyte reactivation within the CNS compartment. Although perivascular dendritic cells found in inflammatory lesions are reported to polarize naive CD4+ T lymphocytes into interleukin-17-secreting-cells, the origin of those antigen-presenting cells remains controversial. We demonstrate that a subset of CD14+ monocytes migrate across the inflamed human blood-brain barrier (BBB) and differentiate into CD83+CD209+ dendritic cells under the influence of BBB-secreted transforming growth factor-beta and granulocyte-macrophage colony-stimulating factor. We also demonstrate that these dendritic cells secrete interleukin-12p70, transforming growth factor-beta and interleukin-6 and promote the proliferation and expansion of distinct populations of interferon-gamma-secreting Th1 and interleukin-17-secreting Th17 CD4+ T lymphocytes. We further confirmed the abundance of such dendritic cells in situ, closely associated with microvascular BBB-endothelial cells within acute multiple sclerosis lesions, as well as a significant number of CD4+ interleukin-17+ T lymphocytes in the perivascular infiltrate. Our data support the notion that functional perivascular myeloid CNS dendritic cells arise as a consequence of migration of CD14+ monocytes across the human BBB, through the concerted actions of BBB-secreted transforming growth factor-beta and granulocyte-macrophage colony-stimulating factor.

JAML mediates monocyte and CD8 T cell migration across the brain endothelium

“…Informed consent and ethic approval were given prior to surgery (HD04.046). Primary cultures of BBB‐ECs were established as previously described 6, 7…”

“…peripheral blood mononuclear cells (PBMCs) were isolated, stained, and analyzed as previously reported 7. PBMCs were phenotyped using antibodies (10 mg/mL) specific for human JAML‐FITC (R&D systems), CD3‐APC, CD4‐PE‐Cy7, CD8‐PB, CD14‐PE, and CD19‐Alexa700 or corresponding isotype controls (all from BD Biosciences) (East Rutherford, NJ).…”

“…Monocytes were isolated by positive selection according to the manufacturer's protocol (Miltenyi). Activated CD8 T cells and monocytes (10 6 cells per well) were added to the transwell chamber containing anti‐JAML (R&D systems, 20 μ g/mL) or control immunoglobulins and migrated for 18 h. Migrated cells were imaged using DIC microscopy (Leica MZ10F; Leica Microsystems, Wetzlar ‐ Germany), and were collected and counted as previously described 6, 7, 8…”

Functions of lipid raft membrane microdomains at the blood–brain barrier

“…Lymphocyte and myeloid cell diapedesis across CNS endothelium involves prototypic BBB CAMs such as ICAM-1 and ICAM-2 (for lymphocytes [82,83]) and VCAM-1 (for myeloid cells) [84][85][86] which are expressed on the cell surface and/or at intercellular junctions and can associate with membrane microdomains (Fig. 2c) [87][88][89].…”

IL-12 Family Cytokines in Inflammation and Bone Erosion of Rheumatoid Arthritis

“…However it also suppresses joint inflammation by promoting Th1 cell responses and suppressing Th17 cell responses (Pickens et al, 2011). Because IL-17 production by Th17 cells induces inflammation through recruitment of neutrophils and macrophages (Ifergan et al, 2008;Xie, Jin and Yu, 2007), suppressing Th17 cell responses therefore results in protection against inflammation (Niedbala et al, 2008). The effect of IL-27 on joint inflammation differs depending on the animal model.…”