CCR6 ( CC Chemokine Receptor 6) Is Essential for the Migration of Detrimental Natural Interleukin-17-Producing γδ T Cells in Stroke

Background and Purpose-Immune-mediated tissue damage after stroke evolves within the first days, and lymphocytes contribute to the secondary injury. Our goal was to identify T-cell subpopulations, which trigger the immune response. Methods-In a model of experimental stroke, we analyzed the immune phenotype of interleukin-17 (IL-17)-producing.d T cells and explored the therapeutic potential of neutralizing anti-IL-17 antibodies in combination with mild therapeutic hypothermia. Results-We show that brain-infiltrating IL-17-positive.d T cells expressed the V.6 segment of the.d T cells receptor and were largely positive for the chemokine receptor CCR6 (CC chemokine receptor 6), which is a characteristic for natural IL-17-producing.d T cells. These innate lymphocytes are established as major initial IL-17 producers in acute infections. Genetic deficiency in Ccr6 was associated with diminished infiltration of natural IL-17-producing.d T cells and a significantly improved neurological outcome. In the ischemic brain, IL-17 together with tumor necrosis factor-a triggered the expression of CXC chemokines and neutrophil infiltration. Therapeutic targeting of synergistic IL-17 and tumor necrosis factor-a pathways by IL-17 neutralization and therapeutic hypothermia resulted in additional protective effects in comparison to an anti-IL-17 antibody treatment or therapeutic hypothermia alone. Conclusions-Brain-infiltrating IL-17-producing.d T cells belong to the subset of natural IL-17-producing.d T cells. In stroke, these previously unrecognized innate lymphocytes trigger a highly conserved immune reaction, which is known from host responses toward pathogens. We demonstrate that therapeutic approaches targeting synergistic IL-17 and tumor necrosis factor-a pathways in parallel offer additional neuroprotection in stroke. Visual Overview-An online visual overview is available for this article.