Migratory Cues For Encephalitogenic Effector T Cells Within The CNS During The Different Phases Of EAE

Migratory Cues For Encephalitogenic Effector T Cells Within The CNS During The Different Phases Of EAE

Christian Schläger

Doctoral thesis

Date of Examination: 2013-04-30

Date of issue: 2013-06-17

Advisor: Flügel, Alexander Prof. Dr.

Referee: Reichardt, Holger Prof. Dr.

Referee: Simons, Mikael Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-001E-FE91-A

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Abstract

English

In multiple sclerosis (MS), encephalitogenic T cells are considered to breach distinct cerebral barriers in order to gain access to their target tissue, the CNS. However, it remains poorly understood exactly how auto-reactive T cells overcome these boundaries and which migratory cues guide them on their journey. In the present work, intravital two-photon laser scanning microscopy (TPLSM) was employed to examine in detail the migratory behavior of adoptively transferred GFP+ CD4+ MBP-reactive T cells under the influence of chemokine signaling during different disease phases of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. During preclinical EAE, encephalitogenic effector T cells were crawling along the intraluminal surface of leptomeningeal blood vessels preferentially against the direction of the blood stream. Intravenous administration of pertussis toxin (PTx) or a neutralizing anti-CXCR3mAb revealed that chemokines play an essential role for this intravascular crawling behavior. (1) Intraluminal crawling was almost completely abolished; (2) the remaining fraction of cells profoundly changed their motility characteristics, i.e. they crawled for a shorter time with increased velocity and reversed their orientation to go with instead of against the flow. Once myelin-reactive T cells had transgressed the vascular barriers they continued their migration throughout the meningeal surface. Interference with chemokine signaling at this stage had only a moderate impact on the basal T cell motility. However, chemokines were important for stabilizing the contacts between T cells and resident phagocytes and furthermore prevented the detachment of T cells from the meningeal surface into the cerebrospinal fluid (CSF). In sum, the data indicate that encephalitogenic T cells invade the CNS through a well-coordinated sequence of distinct steps, in which chemokines play a major role. Chemokines regulate effector T cell infiltration by controlling adhesion-dependent migratory steps and intercellular interactions during CNS inflammation.

Keywords: EAE; MS; Chemokines; T cells; TPLSM; intravascular crawling