title: Cytomegalovirus-induced effector T cells cause endothelial cell damage.
abstract: Human cytomegalovirus (CMV) infection has been linked to inflammatory diseases that involve vascular endothelial cell damage, but definitive proof for a direct cytopathic effect of CMV in these diseases is lacking. CMV infection is associated with a strong increase in both CD4(+) and CD8(+) T cells with constitutive effector functions that can perpetuate systemic inflammation. We investigated whether CMV-induced immune responses could lead to endothelial damage in humans. We found that terminally differentiated effector CD4(+) and CD8(+) T cells, formed during primary CMV infection and maintained throughout latency, express high levels of CX3CR1 and CXCR3. The ligands of these receptors, fractalkine and IP-10, respectively, are expressed by activated endothelial cells. Peripheral blood mononuclear cells (PBMC) stimulated with CMV antigen produced soluble factors that stimulated endothelial cells to produce both chemokines. Finally, effector cells migrated in a fractalkine- and IP-10-dependent fashion to activated endothelial cells and induced apoptosis in endothelial cells that were stimulated by supernatant from CMV-activated PBMC. Our findings offer an explanation for the accumulation of highly differentiated T cells near to the endothelium in CMV-infected individuals that may result in endothelial damage.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Pablo J E J
authors.initials: PJ
authors.lastname: van de Berg
authors.forename: Si-La
authors.initials: SL
authors.lastname: Yong
authors.forename: Ester B M
authors.initials: EB
authors.lastname: Remmerswaal
authors.forename: René A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: Ineke J M
authors.initials: IJ
authors.lastname: ten Berge
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1 / Q000096:biosynthesis; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology* / Q000472:pathogenicity*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology*; D042783:Endothelial Cells / Q000276:immunology / Q000821:virology*; D015870:Gene Expression; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D054367:Receptors, CXCR3 / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054428:Chemokine CX3CL1; D054357:Chemokine CXCL10; D016207:Cytokines; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine