Fractalkine Induces the Expression of Intercellular Adhesion Molecule-1 on CD4+ T-lymphocytes: implications for the immunopathogenesis of Multiple Sclerosis Public Deposited

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  • March 20, 2019
Creator
  • Blauth, Kevin
    • Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum
Abstract
  • Fractalkine (CX3CL1) is a chemokine that has been shown to play roles in lymphocyte chemotaxis, inflammation, and neuroprotection in central nervous system (CNS) diseases. Here we examined roles for CX3CL1 in CD4+ T-cell chemotaxis mediated via their upregulation of adhesion molecule expression as well as secretion of inflammatory cytokines involved in the pathogenesis of relapsing remitting multiple sclerosis (RRMS). We found that CX3CL1 concentrations are elevated in the cerebrospinal fluid (CSF) of RRMS patients, and that CX3CL1 increases mRNA expression of IFN-γ and TNF-α, and protein secretion of IFN-γ by CD4+ T-cells derived from RRMS patients but not those derived from healthy controls (HCs). We also show that blood-derived CD4+T-cells express increased surface levels of CX3CL1 receptor (CX3CR1) and intercellular adhesion molecule (ICAM)-1 in RRMS patients in comparison to HCs. Furthermore, the percentage of CX3CR1+ICAM-1+CD4+ T-cells are increased in the CSF of untreated RRMS patients in comparison to their peripheral blood samples, and CD4+ T-cells which migrate in-vitro toward a CX3CL1 gradient express higher levels of ICAM-1 than CD4+ T-cells that do not migrate. Furthermore, we demonstrated that CX3CL1 upregulates ICAM-1 expression on the surface of RRMS patient-derived but not HC derived CD4+ T-cells. Lastly, we show that CX3CL1 stimulates ICAM-1 expression on myelin-antigen-specific CD4+ T-cell lines derived from RRMS and healthy donors. These results indicate that CX3CL1 may preferentially recruit CX3CR1+ICAM-1+CD4+ T-cells into the CNS during RRMS development, and may activate CD4+ T-cells to express higher levels of ICAM-1, as well as the proinflammatory cytokines IFN-γ and TNF-α.
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  • In Copyright
Advisor
  • Markovic-Plese, Silva
Degree
  • Doctor of Philosophy
Graduation year
  • 2012
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