The role of T cells in exercise-induced recovery after stroke

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Background and preliminary dataExercise therapy improves the neurological recovery following stroke. In addition, exercise modulates the immune system in healthy subjects and attenuates the inflammatory response in various disease models. In our preliminary experiments, we demonstrated that T cells, especially regulatory T cells (Tregs), are a prerequisite for exercise-enhanced stroke recovery after photothrombotic stroke in mice. Our preliminary findings also showed that exercise influences the occurrence of T cells, astrocytes and microglia. In particular, we found an increase of Tregs in cervical lymph nodes and brain parenchyma in mice subjected to exercise therapy after stroke. Further experiments showed a strong impact of exercise on the activity of cortical neurons. Most importantly, we found a normalization of stroke-induced hyperexcitability of periinfarct neurons in response to physical exercise.ObjectivesOur proposed project shall illuminate the interplay between exercise, T cells and neuronal plasticity following stroke. We will analyze effects of exercise therapy on T cell localization in the ischemic brain and the molecular and functional analysis of T cell-dependent effects of exercise. Finally, we will determine T cell-mediated exercise effects on neuronal plasticity, i.e. axonal sprouting and neuronal excitability.Work programThe temporal and spatial distribution of T cells and their subsets in the ischemic brain and meninges in exercise and control animals will be compared using immunohistochemistry, flow cytometry and whole brain 3-D imaging. Gene expression profiles of T cell subsets and detailed functional analysis including activation, migration, metabolism and signaling will be performed. To further clarify the role of Tregs for exercise-enhanced stroke recovery, we will deplete them at different time points in DEREG mice. In parallel, non-functional Tregs from scurfy mice will be compared to wild type Tregs regarding their ability to mediate exercise effects in Rag1-/- mice after stroke. Antigenic-specificity will be investigated by using 2D2/Rag1 mice. Axonal plasticity of corticospinal tract neurons will be analyzed following stereotactic injection of axonal tracers. To complement axonal plasticity studies, the effect of exercise therapy on the translatome of cortical layer 5 pyramidal neurons will be analyzed in Glt25d2 bacTRAP mice. Effects on neuronal activity and connectivity will be determined by electrophysiological experiments, including single-cell patch-clamp recordings, voltage-sensitive dye experiments, neuronal Ca2+-imaging, and in vivo electrophysiology.ConclusionsOur proposed experiments shall clarify the role of T cells for exercise-mediated long-term recovery following ischemic stroke, thus providing the basis for future recovery-enhancing therapies that modulate identified molecular targets – so called exercise mimetics.