Introduction: Inflammation plays a critical role in the pathogenesis of ischemic stroke. The CNS responds to ischemic injury with an inflammatory process, characterized by an infiltration of inflammatory cells. Particularly T cells exhibit a great impact on early stroke outcome as recent studies showed that ablation of these cells decrease infarct size and improve neurological deficits in the acute phase after stroke. However, the role of T cells in the sub-acute and chronic phase after stroke is unknown. T cells are essential for effective neurogenesis and angiogenesis, mechanisms that are integral for successful regeneration after stroke. We assessed the hypothesis that T cells influence cellular mechanisms of post-ischemic neuroregeneration and consequently affect functional and structural recovery.
Methods: 24 wild type (wt) and 11 RAG1 -/- mice were subjected to photothrombotic ischemia, a subset of 12 wt and 6 RAG1 -/- animals underwent training in motorized running wheels starting at day 3 following ischemia until the end of the experiment on day 28. Sensorimotor and cognitive testing was applied to quantify the recovery process. To label newly generated neurons, 5-Chloro-2′-deoxyuridine (CldU) and iododeoxyuridine (IdU) were administered at days 1 and 2 (CldU) and once weekly until day 28 (IdU) after ischemia. In a subsequent experiment, 17 RAG1 -/- mice were subjected to photothrombotic ischemia and underwent training, a subset of 10 animals received an adoptive transfer of T cells. Functional testing and cellular labeling were carried out in analogy to the first experiment.
Results: Training improved recovery from sensorimotor and cognitive deficits following cortical ischemia in wt animals and increased the generation of new neurons in the ischemic brain. Rehabilitative training did not induce functional recovery in RAG1 -/- animals and had no effect on the generation of neurons. Adoptive transfer of T cells into the immunodeficient mice restored the ability for regeneration.
Conclusion: T cells play an essential role in the functional and structural regeneration following ischemic brain injury. These results provide new clues on the complex mechanism by which immune cells impact different stages of the pathogenesis of ischemic stroke.