Differential Regulation of CD4+ T Cell Adhesion to Cerebral Microvascular Endothelium by the β-Chemokines CCL2 and CCL3

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.

Differential induction of CCL5 by pathogenic and non-pathogenic strains of West Nile virus in brain endothelial cells and astrocytes

“…However, monocyte attachment was increased twofold in WNV-MAD78-infected cultures, which is consistent with the observation that this virus induced higher levels of CCL5 expression in HBMECs compared with WNV-NY. As expected, high levels of THP-1 cells bound to control cells treated with TNF-α ( Liu & Dorovini-Zis, 2012 ). Together, these findings suggest that the chemokine response in HBMEC monolayers to non-pathogenic strains of WNV may be more efficient at attracting leukocytes compared with highly pathogenic strains of WNV.…”

Zika Virus Infection Promotes Local Inflammation, Cell Adhesion Molecule Upregulation, and Leukocyte Recruitment at the Blood-Brain Barrier

“…Interestingly, it was also detected in plasma samples from ZIKV + patients (our results and those in reference 39 ). Moreover, CCL5 and CCL2 are known mediators of leukocyte recruitment to the BBB ( 57 , 58 ), thus suggesting that the local environment in ZIKV-infected BBB could favor immune cell recruitment/migration and access to the CNS. Besides the upregulation of chemoattractants, one of the key observations of this study was the marked increase in CAM expression, namely, ICAM-1, VCAM-1, and E-selectin, in ZIKV-infected hBLECs.…”

Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression

“…We found that the expression of specific cell adhesion molecules was induced exclusively in Cup/EAE mice, suggesting that these treatments have produced an environment conducive to inflammatory cell activity. Moreover, we identified upregulation of Ccl2 , Ccl3 , and Cxcl10 , which encode chemokines that act as chemoattractants for various inflammatory cells, including T lymphocytes (Carr, Roth, Luther, Rose, & Springer, ; K. K. Liu & Dorovini‐Zis, ; Millward, Caruso, Campbell, Gauldie, & Owens, ), dendritic cells (Xu, Warren, Rose, Gong, & Wang, ), monocytes (Moreno et al, ; Price et al, ), and microglia (Clarner et al, ; Moreno et al, ). Interestingly, the cerebella of mice showed relatively weaker induction of these chemokines, despite that obvious involvement of this region in EAE by our work and those of others.…”