Understanding immune cell trafficking at cellular and molecular level

• Applicant: Professorin Dr. Francesca Odoardi
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416987258

The aim of this project is to follow the behavior and function of autoaggressive T cells in the central nervous system (CNS). The studies focus particularly on the question of how pathogenic T cells can specifically attack certain tissues, namely the grey or white matter in the CNS. In my studies to date, I have already been able to gain new insights into the ports of entry and the rules that determine the invasion of the autoaggressive T cells. For example, I was able to show that 1) T cells enter the spinal cord white matter and the brain grey matter via the leptomeninges, but not the dura, 2) that the activation of autoreactive T cells within the tissue determines where the inflammatory lesions within the tissue are located, and 3) that lung microbiota play a major role in determining the entry of autoaggressive T cells into both the grey and white matter, namely by controlling the immunoreactivity of microglia. In addition, the studies uncovered new and unexpected properties of cerebral blood vessels. They showed that effector T cells attach more strongly to leptomeningeal than to dural vascular endothelia, although leptomeningeal vessels are, similar to cerebral vessels, sealed by tight junctions, whereas dural vessels are fenestrated like vessels of the periphery and should favor the passage of immune cells. Interestingly, however, leptomeningeal vessels adjacent to the grey matter also differed from those adjacent to the white matter. Against this background, in the continuation period of this proposal, I will identify molecular factors responsible for the observed uniqueness of leptomeningeal vessels. To this end, the properties of different vessels will be compared at the functional and molecular level under physiological conditions. Technologies and approaches developed within the framework of the Heisenberg professorship (see parallel application) will be used for this purpose. Specifically, the combination of intravital imaging, super-resolution techniques and transcriptomic will be used to investigate the motility behavior of immune cells in their respective vascular beds, to characterize the spatial distribution of adhesion molecules in individual vascular beds at the single cell level and to analyze how the heterogeneity of these molecules between and within tissues influences the trafficking of immune cells. Finally, the observations will be confirmed in human samples. Conceptually, these data will allow us to understand the general and local rules that regulate immune cell trafficking in different vascular beds and specifically in the CNS. Technically, the ability to spatially correlate molecular and functional information will set the stage for understanding mechanisms that regulate the behavior of immune cells in different vascular compartments in different pathological conditions.

• DFG Programme: Research Grants