Abstract
In Multiple sclerosis (MS), circulating lymphocytes cross the blood–brain barrier (BBB) and accumulate at sites of antigenic challenge. This process depends on specific interactions between lymphocytes and cerebral microvascular endothelium that involve endothelial activation by cytokines and the presence of chemokines. Chemokines play a key role in the orchestration of immune responses, acting both as chemoattractants and activators of leukocyte subsets. In the present study, we investigated the effects of the β-chemokines, CCL2 and CCL3, on the adhesion of CD4+ T cell subsets to human brain microvessel endothelial cells (HBMEC). Chemokines added to the lower compartment of a two-chamber chemotaxis system under confluent resting or cytokine-activated HBMEC, diffused through the culture substrate and bound to the basal surface of HBMEC. The low rate of adhesion of naïve, resting and memory CD4+ T cells to resting HBMEC was significantly upregulated following treatment of HBMEC with TNF-α and IFN-γ. Recently activated CD4+ T cells readily adhered to resting monolayers. Concentration gradients of CCL2 upregulated the adhesion of activated CD4+ T cells to cytokine treated but not resting HBMEC. The presence of CCL3 in the lower chamber increased the adhesion of memory T cells to both unstimulated and cytokine-treated HBMEC. These findings emphasize the importance of brain endothelial cell activation and the role of CCL2 and CCL3 in regulating the adhesion of CD4+ T cell subsets to BBB endothelium, thus contributing to the specificity of immune responses in MS.
Highlights
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized pathologically by discrete areas of inflammation, demyelination and variable axonal damage
We demonstrate that the presence of CCL2 or CCL3 concentration gradients across the monolayers differentially regulates T cell adhesion and this effect is dependent upon the subset of T
The rate of diffusion of CCL2 and CCL3 across confluent human brain microvessel endothelial cells (HBMEC) monolayers in the presence of chemokine gradients was determined in a double-chamber chemotaxis system using radiolabeled chemokines
Summary
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized pathologically by discrete areas of inflammation, demyelination and variable axonal damage. Under inflammatory conditions, signaling events induced by proinflammatory cytokines lead to profound molecular, functional and morphological alterations of cerebral endothelial cells Prominent among these changes is the de novo expression and upregulation of endothelial cell adhesion molecules and chemokines which, through specific interactions with corresponding ligands on leukocytes, provide the necessary cues for their adhesion and migration across the BBB. We demonstrate that the presence of CCL2 or CCL3 concentration gradients across the monolayers differentially regulates T cell adhesion and this effect is dependent upon the subset of T cells and the activation state of the BBB endothelium
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.