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Effects of desialyation on TCR-cross-linking and antigen sensitivity of CD8 positive T lymphocytes
(2005)
The featured experiments focus on changes in T cell membrane glycosylation as a possible means of controlling TCR cross-linking. Taking the long known fact that activated T cells show decreased levels of surface sialic acid as a starting point, differences in ligand binding and cellular reaction upon in vitro stimulation were investigated in naïve, activated and enzymatically desialyated CD8+, 2C TCR transgenic mouse lymphocytes. To detect differences in ligand binding lymphocytes were incubated with various concentrations of fluorescently labeled, soluble MHC/Ig fusion proteins until equilibrium was reached. Without previous washing, cells were analyzed by flow cytometry, determined MCF values were normalized to the plateau and fit to a mathematical model of equilibrium binding of divalent ligands to monomorphic receptors (Perelson 1984). Parameters derived from the model fit of binding data show, that neuraminidase treatment of T cells was sufficient to mimic a partially activated phenotype, showing enhanced TCR cross-linking. Enhanced TCR cross-linking was found to be dependent on the presence of CD8, as neuraminidase treatment of DN cells lead to decreased cross-linking. To elucidate the physiological relevance of desialyation induced increases in TCR cross-linking early tyrosine phosphorylation events and proliferative response upon in vitro stimulation of T cells were investigated. Both were found enhanced in neuraminidase treated cells, as compared to native cells. In conclusion the featured experiments suggest a role of surface sialic acid in controlling TCR cross-linking on naïve and activated T cells.
Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4\(^+\) T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A\(_2\) were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS.