CNS antigen-specific CD4+ T cells as modulators of inflammation and regeneration in stroke

• Applicants: Dr. Antonella Carambia; Dr. Mathias Gelderblom
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564636838

Ischemic stroke is a major cause of disability and mortality worldwide. Long-term stroke outcome is substantially determined by the post-ischemic neuroinflammatory response, which can thus far not be effectively targeted by current therapies. Here we address the role of autoreactive CD4+ T cells that recognize CNS antigens, which are extensively released during stroke-induced tissue damage. Myelin-specific CD4+ T cells have a proven pathogenic role in autoimmune neuroinflammation. However, in contrast to their pathogenic potential in autoimmune disease, our preliminary findings demonstrate that myelin-specific CD4+ T cells induced significant neuroprotection in experimental stroke as reflected by smaller infarct volumes and significantly reduced tissue inflammation, as compared to non-specific CD4+ T cells. Moreover, we found that myelin-specific CD4+ T cells induced a distinct gene expression pattern in reactive microglia, indicating that tissue protection was dependent on myelin-specific CD4+ T cell – microglia interaction. Therefore, we hypothesize that myelin-specific CD4+ T cells adapt their functionality to the ischaemic condition, and promote long-term neuroregeneration after ischemic stroke by modulating the inflammatory activation of reactive tissue-resident cells, notably microglia and astrocytes. The objective of this proposal is to identify cellular and molecular mechanisms that qualify as treatment targets, by 1) analysing the functional differences between myelin-specific T cells in stroke, in comparison to their counterparts in experimental autoimmune encephalomyelitis (EAE), 2) characterising the interplay of myelin-specific CD4+ T cells with reactive tissue-resident cells in stroke, and 3) assessing the functional consequences thereof for the post-stroke immune response and long-term regeneration.

• DFG Programme: Research Grants