Brain-invading T cells as regulators of microglial function in stroke

• Applicant: Dr. Corinne Benakis
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418128679

Neuroinflammatory mechanisms contribute substantially to the pathophysiology of acute brain injuries such as stroke. Key components of neuroinflammation stroke conditions are the activation of resident microglial cells as well as the invasion of circulating leukocytes into the brain. Particularly T cells have been demonstrated to be the most potent peripheral leukocyte subpopulation contributing to the progression of neurodegeneration. However, the interaction of these two key immune cell populations—microglia and T cells—is still barely understood. Previous studies investigating their interaction have focused on the role of microglia as antigen-presenting cells in activating brain-invading T cells. Yet, preliminary results from our group demonstrate that vice versa cerebral T cells have a substantial effect on microglial activation and polarization. Pro-inflammatory T cells have been shown to promote neurotoxic activity while regulatory T cells have a modulatory function on secondary neuroinflammation. Therefore, we hypothesize that microglial function is substantially regulated by invading T cells under stroke conditions. To test this concept, we will model post-stroke neurodegeneration by experimental middle cerebral artery occlusion. The role of T cells will be investigated by: a) genetic lymphocyte deficiency and b) cisterna magna injection of specific T cell subpopulations into T cell deficient mouse recipients. Microglial homeostasis and polarization will be analyzed by transcriptomic analysis using previously established NanoString gene sets for differentially regulated genes. Changes in microglial morphology after T cell interaction will be investigated by a novel technology of multiparametric shape descriptor analysis. Importantly, the role of microglia as mediators of T cells’ effects on stroke outcome will be tested by behavioral tests and infarct volumetry as pathological hallmarks of stroke disease . This study will address a key question in the field of neurodegeneration—the modulation of microglial activity by brain-invading T cells—which is of direct clinical relevance. Tools for T cell polarization have been well established in models of autoimmune diseases and therapeutic options are readily available. Thereby, T cells hold the potential to function as ‘Trojan horses’ with large impact on the cerebral inflammatory milieu which is potentiated by microglial cells. Hence, this work will provide new insights into the pathophysiological mechanisms of stroke with the potential for the identification of novel drug targets.

• DFG Programme: Research Grants