Glutamate receptor signaling is critical for T cell function and antitumor activity

Abstract

Abstract The interaction between the nervous system and immune system has sparked interest in recent years. Emerging evidence shows an intricate neuroimmune network. We were intrigued by the expression of various neurotransmitter receptors on T lymphocytes. Specifically, following TCR stimulation, glutamate receptors (GluR) were significantly upregulated on both CD4+ and CD8+ T cells, with a peak at 48 h. Concomitant with the upregulation of activation molecules CD69, CD25 and CD44, proliferating CD8+ T cells presented higher levels of GluA3 and mGluR1 when compared with resting cells. By blocking group I metabotropic glutamate receptors and AMPA receptors through antagonists, we show that CD8+ T cells have a delayed activation but their viability is not altered. However, GluR blockade affected CD8+ T cell proliferation and their ability to kill tumor cells in vivo or target cells in vitro. While the frequency of GluR+CD8+ T cells ranges around 30% of total CD8+ T population, the effect of blocking glutamate signaling through receptor antagonists is a dominant effect and it is mediated by transient reduction in protein phosphorylation of TCR mediated pathways as well as calcium modulation. Overall, data suggest that glutamate receptors may have a stimulatory effect on T cell activation and glutamate agonists may boost T cell response in an immunosuppressive setting such as cancer.