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Influences on T cell Migration Behavior in the Inflamed Brain

Creative Commons 'BY-NC-SA' version 4.0 license

Cell migration is an integral function of immunity. Control of cellular infiltration and behavior are critical to prevent inflammation-induced pathology while still combating infection. Nowhere in the body is this balance more important than the CNS. As an immune privileged site, the brain needs a potent response that is compatible with the surrounding sensitive tissue. Chronic infection with the parasite Toxoplasma gondii provides a model of balance. T cells must migrate efficiently within the brain to find sites of infection and keep parasites from replicating. Many factors can influence cell behavior once leukocytes enter the brain. This dissertation examines the role two molecules play in T cell migration during chronic Toxoplasma infection.

First, the role of the intracellular adaptor protein β-arrestin 2 (β-arr2) is examined in T cell migration in response to the chemokine CCL21. β-arr2 is required for migration of naïve cells and those isolated from the brain. Chemotaxis studies demonstrate this requirement is a result of mediating migratory speed. Next, β-arr2’s role in cell trafficking to infected tissue is tested in vivo. Finally, using two-photon microscopy β-arr2 is shown to mediate migratory speed of infiltrating T cells in the brain. Together these data define the specific role for β-arr2 in regulating T cell velocity in the CNS.

Next, the effect of the matricellular glycoprotein SPARC is discussed. Infected astrocytes are the source of SPARC in the infected brain, the same source as CCL21. Novel binding partners for SPARC- CCL21 and CCL19- are reported, expanding the potential roles of SPARC to include the maintenance of chemokine signals in the brain. SPARC’s presence enhances T cell migration in response to CCL21. Finally, two-photon imaging reveals SPARC enhances T cell access to the brain and slightly enhances T cell migration behavior within the brain. These data demonstrate how SPARC cooperates with other proteins in the brain matrix to contribute to T cell behavior.

Lastly, additional levels of regulation for chemokine dependent cell migration are considered and potential areas of further investigation are proposed. This dissertation provides new insight into T cell migration during a protective immune response in the brain.

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