Functional role of regulatory lymphocytes in stroke: facts and controversies.

T he secondary neuroinflammatory response has attracted increasing attention in experimental stroke research. 1 Analyses of immunologic mechanisms after acute stroke have been performed in the hope of identifying key pathomecha-nisms that contribute to secondary infarct growth and can be modulated to benefit a large proportion of patients with stroke. Among a variety of pathophysiologic mechanisms, including microglial activation, brain leukocyte invasion, and secretion of proinflammatory factors, lymphocytes have been uncovered as the key leukocyte subpopulation that determines the neuroinflammatory outcome. Several studies have shown that proinflammatory lymphocytes, such as TH1, TH17, and γδ T-cells, worsen stroke outcome, and that blocking of their brain invasion is neuroprotective. 2–4 Contrary to proinflamma-tory lymphocytes, regulatory T-cells (Treg) and B-cells (Breg) have been characterized as disease-limiting protective cells 5 ; in particular, in primary inflammatory diseases of the central nervous system. The discovery of the important role of Treg in other T-cell–driven pathologies has initiated productive research efforts on the role of Treg, including in ischemic brain injury, over the past years. However, because of the complex function of regulatory cells in immune homeostasis and disease, as well as partially divergent findings using different stroke models, uncertainty has emerged about the patho-physiologic function of regulatory lymphocytes in stroke. 6–8 This article will comprehensively review current findings on regulatory lymphocytes in brain ischemia models and discuss potential reasons for the observed discrepancies. The immune system has evolved several regulatory mechanisms , including cell depletion, anergy, and unresponsiveness to autoantigens, to prevent damage of endogenous tissues because of an overshooting immune reaction. The presence of Treg actively suppressing autoimmune reactivity is one of the key mechanisms preserving immune homeostasis and limiting inflammatory collateral damage. + CD4 + Treg naturally arising in the immune system induces autoim-mune diseases, and reconstitution of this cell population prevents disease development. 10 A lack of Treg has been shown to be a primary cause of autoimmune diseases in humans. 11 In addition to sustaining autotolerance, Treg are also involved in suppressive control of a broad spectrum of immune responses, including those against autologous tumor cells, 12 allergens, 13 and organ transplantation. 14 Although Treg might be simplis-tically defined as immunosuppressive T-cells, several pheno-typically and functionally distinct Treg subpopulations have been defined, such as induced Treg populations, Tr1, TH3, and various others. 15 Yet, the best investigated population of Treg are CD4 + CD25 + Foxp3 + naturally occurring Treg, which …