CON: Regulatory T Cells Are Protective in Ischemic Stroke

or many years ischemic stroke was regarded as a purely thrombotic disease resulting from the occlusion of cere-bral arteries and subsequent breakdown of energy supply to neuronal tissues. Back in the late 1970, however, some pioneers in experimental stroke research, above all John Hallenbeck at the National Institute of Neurological Disorders and Stroke recognized the existence of polymorphonuclear leukocytes and macrophages in brain specimen from animals and patients with cerebral ischemia, thereby establishing the conceptual basis for the immunobiology of stroke. 1 Since then a plethora of experimental studies stressed the importance of these typically innate immune cells in brain ischemia but clinical trials testing, for example, neutrophil blocking agents, ultimately bombed. Several years later Stoll and Jander 2 from Düsseldorf, Germany, were among the first to describe the infiltration of T lymphocytes, which per definition belong to the adaptive immune system, into ischemic brains of rodents. Of note, this happened accidentally while searching for a central nervous system lesion paradigm devoid of inflammation which could be used as control for experimental autoimmune encephalomyelitis. It is meanwhile well accepted that T cells exert deleterious effects in brain ischemia. However, the functional relevance of the different T cell subsets for stroke progression is less clear, as is their pathological contribution at the different stages of infarction (ie, acute versus chronic). In particular, a controversial dispute recently arose on the function of regulatory T cells (Tregs) in the ischemic brain. In a rather simplistic view, many people think about Tregs as the good immune cells which without exception maintain immune tolerance and counteract tissue damage in a variety of (neurological) diseases, such as multiple sclerosis. However, biology usually does not follow a plain black and white dichotomy, and in most situations an exception to the rule exists. In the case of Tregs this exception is isch-emic stroke. Using a mouse model of selective Tregs depletion (Depletion of Regulatory T cells [DEREG] mice), we could unambiguously show that Tregs are strong promoters of ischemic neurodegeneration. 3 Depletion of Tregs dramatically reduced infarct size and improved neurological function 24 hours after 60 minutes of transient middle cerebral artery occlusion, and this protective phenotype was preserved at later stages of infarct development (until day 7) and in models of mild ischemic stroke. Mechanistically, Tregs induced micro-vascular dysfunction in vivo by increased interaction with the ischemic brain endothelium and platelets. Accordingly, ablation of Tregs reduced microvascular …