β1-Integrin– and KV1.3 channel–dependent signaling stimulates glutamate release from Th17 cells
Katharina Birkner, Beatrice Wasser, Tobias Ruck, Carine Thalman, Dirk Luchtman, Katrin Pape, Samantha Schmaul, Lynn Bitar, Eva-Maria Krämer-Albers, Albrecht Stroh, Sven G. Meuth, Frauke Zipp, Stefan Bittner
Katharina Birkner, Beatrice Wasser, Tobias Ruck, Carine Thalman, Dirk Luchtman, Katrin Pape, Samantha Schmaul, Lynn Bitar, Eva-Maria Krämer-Albers, Albrecht Stroh, Sven G. Meuth, Frauke Zipp, Stefan Bittner
View: Text | PDF
Research Article Autoimmunity Neuroscience

β1-Integrin– and KV1.3 channel–dependent signaling stimulates glutamate release from Th17 cells

Abstract

Although the impact of Th17 cells on autoimmunity is undisputable, their pathogenic effector mechanism is still enigmatic. We discovered soluble N-ethylmaleimide–sensitive factor attachment receptor (SNARE) complex proteins in Th17 cells that enable a vesicular glutamate release pathway that induces local intracytoplasmic calcium release and subsequent damage in neurons. This pathway is glutamine dependent and triggered by binding of β1-integrin to vascular cell adhesion molecule 1 (VCAM-1) on neurons in the inflammatory context. Glutamate secretion could be blocked by inhibiting either glutaminase or KV1.3 channels, which are known to be linked to integrin expression and highly expressed on stimulated T cells. Although KV1.3 is not expressed in CNS tissue, intrathecal administration of a KV1.3 channel blocker or a glutaminase inhibitor ameliorated disability in experimental neuroinflammation. In humans, T cells from patients with multiple sclerosis secreted higher levels of glutamate, and cerebrospinal fluid glutamine levels were increased. Altogether, our findings demonstrate that β1-integrin– and KV1.3 channel–dependent signaling stimulates glutamate release from Th17 cells upon direct cell-cell contact between Th17 cells and neurons.

Authors

Katharina Birkner, Beatrice Wasser, Tobias Ruck, Carine Thalman, Dirk Luchtman, Katrin Pape, Samantha Schmaul, Lynn Bitar, Eva-Maria Krämer-Albers, Albrecht Stroh, Sven G. Meuth, Frauke Zipp, Stefan Bittner

×

Figure 10

Intrathecal administration of glutaminase inhibitor CB-839 ameliorates disease course of EAE, and inhibition of Kv1.3-mediated pathways modulates direct cell-cell contacts between T cells and neurons.

Options: View larger image (or click on image) Download as PowerPoint
Intrathecal administration of glutaminase inhibitor CB-839 ameliorates d...
(A) Intracellular staining of IL-17 in murine Th17 differentiated cells after 10 days TCR stimulation (n = 6–7). d10, day 10. (B) Passive cell transfer EAE with MOG-reactivated lymph node cells from KCNA3–/– mice (n = 6) compared with EAE induction with MOG-reactivated lymph node cells from WT mice (n = 9 for 2 independent EAE experiments). (C) B6.2D2.RFP.Th17 cells were transferred into Rag–/– mice to induce passive EAE. Two-photon microscopy was used to analyze T cell motility parameters of viable B6.2D2.RFP.Th17 cells before treatment (n = 6 mice; minimum of 30 T cells) and after MgTX treatment (5 μM; n = 7 mice; minimum of 30 T cells). The treatment was locally applied onto the brainstem. Stationary cells were defined by a displacement rate below 0.3 μm/s, low-motility cells reached displacement rates up to less than 0.8 μm/s, and high-motility cells had a displacement rate above 0.8 μm/s. (D) In MOG35–55-induced C57BL/6 EAE mice, intrathecal injection of CB-839 (5 μM in 5 μL/mouse, n = 8) into the CSF every other day for 14 days, starting on day 7, led to a significant reduction in the clinical EAE score compared with the PBS-treated control group (n = 8 for 2 independent EAE experiments). Data indicate the mean ± SEM. *P < 0.05, by multiple Student’s t tests (B and D) or Mann-Whitney U test (A and C).