Stroke is caused by a loss of blood flow to the brain, in some cases resulting in permanent neurological damage. Unfortunately, there is no FDA-approved neurotherapeutic to reverse this damage and promote functional recovery. Our previous research has made significant advances in understanding the neuro-immunological interplay by demonstrating the possible opposing roles that immune cells play during stroke recovery. My previous research showed that B-cells ameliorate stroke severity, while novel neuronal-reactive CD8+ T-cells were robustly activated following an ischemic injury (the focus of this project). CD8 T-cells are potentially detrimental as their function includes cytotoxicity to target cells, and in the case of stroke, the very cells which are undergoing repair. Our preliminary data show that CD8 T-cells are reactive to a neuronal peptide in multiple mouse strains. These CD8 T-cells are inflammatory, and infiltration into the CNS by these CD8 T-cells correlates with a decrease in motor function recovery. In fact, in a pediatric patient cohort, we observed CD8 T-cell reactive to brain antigens only in patients with heart/lung treatment which subsequently developed brain injury.

The proposed project will investigate the role of stroke-induced GluN2A (neuronal)-specific CD8+ T-cells as secondary mediators of neuronal cell death following an ischemic injury, thus inhibiting endogenous motor function recovery. We will characterize these cells and determine if they can indeed directly cause neuronal cell death. We will also determine if these cells can cause motor/behavior dysfunction in vivo, a phenomenon that is not directly dependent on neuronal killing.

In summary, we will delineate the cellular targets, mechanisms, and motor/behavior dysfunction stroke-induced neuronal-reactive CD8 T-cells possess using in vitro and in vivo approaches. Investigating the immune mechanisms that may potentiate an ischemia-induced brain injury is a novel approach to understanding how the immune system can be targeted in order to maximize recovery from a neurovascular disease that affects millions of people each year.