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NKT CELLS IN ALTERED IMMUNE STATUS FOLLOWING STROKE INJURY
C Wong, P KubesUniversity ofCalgary, Calgary, Alberta
AIMS: Natural Killer T (NKT) cells were first recognised more than a decade ago as a distinct lymphocyte lineage that regulates a broad range of immune responses. It has been proposed that NKT cells are vital to bridge the innate and adaptive immune system by their ability to promptly release Th1 (IFNgamma) or Th2 (IL-4) cytokines and interact with a variety of cells to function as a master regulator of immunity. Only recently with the aid of intravital spinning disk microscopy and the generation of CXCR6-GFP mice which express GFP in NKT cells, we were able to visualise that NKT cells reside and crawl or "patrol" within the liver vasculature to constantly sample the blood for infections but also perhaps endogenous injurious or danger signals. Despite a growing body of evidence that suggests the central nervous system and immune system are closely linked, the role of NKT cells in systemic immunity and inflammatory response following a cerebral ischemia-reperfusion injury (stroke) is unclear. Severe strokes in humans are associated with a rapid increase of circulating IL-10 in plasma prior to the appearance of stroke associated infection. This may be a systemic repercussion that occurs in response to post-ischemic inflammation in the brain. We aim to investigate the role of NKT cells in altered systemic immune status following a stroke.
METHODS: Mouse model of stroke was induced via the intraluminal occlusion of the mid-cerebral artery. Using CXCR6-GFP mice and intravital spinning disk microscopy, we observed a substantial change in the behavior of NKT cells following a stroke.
RESULTS: Following ischemic injury to the brain NKT cells cease their trademark intravascular crawling and stopped patrolling the liver sinusoids. The levels of IFNgamma, a cytokine important for clearance of infections and hallmark of NKT cell activation, did not increase after an ischemic event in the brain. In addition, an increase of serum IL-10 levels in the post-ischemic mice precedes the altered NKT behavior. Previous studies have shown that the activation of the sympathetic nervous system following a stroke induces pronounced systemic immunological changes. By blocking this activation with propranolol (beta-blocker), the altered behavior of NKT cells post stroke was reversed. It is anticipated that propranolol treatment inhibited the anti-inflammatory cytokine (IL-10) release into the systemic circulation, allowing the NKT cells to patrol within liver sinusoids and sample the blood for stroke associated infections.
CONCLUSIONS: Therefore, NKT cells contribute significantly to the altered immune response following a stroke, conceivably by controlling stroke associated infection and modulate the post-stroke systemic inflammatory response. Considering the currently limited therapies to manage infections in stroke patients, this research can significantly improve on the clinical outcome of stroke patients.