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. 2017 Jul;48(7):1957-1965.
doi: 10.1161/STROKEAHA.117.016753. Epub 2017 Jun 13.

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

Priyadharshini Arunachalam  1 , Peter Ludewig  1 , Patrick Melich  1 , Thiruma Valavan Arumugam  1 , Christian Gerloff  1 , Immo Prinz  1 , Tim Magnus  1 , Mathias Gelderblom  2
Affiliations

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

Priyadharshini Arunachalam et al. Stroke. 2017 Jul.

Abstract

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 γδ 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 γδ T cells expressed the Vγ6 segment of the γδ 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 γδ 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 γδ T cells and a significantly improved neurological outcome. In the ischemic brain, IL-17 together with tumor necrosis factor-α triggered the expression of CXC chemokines and neutrophil infiltration. Therapeutic targeting of synergistic IL-17 and tumor necrosis factor-α 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 γδ T cells belong to the subset of natural IL-17-producing γδ 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-α pathways in parallel offer additional neuroprotection in stroke.

Keywords: brain; interleukin-17; lymphocytes; neuroprotection; stroke.

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