Neurotransmitter signalling via NMDA receptors leads to decreased T helper type 1‐like and enhanced T helper type 2‐like immune balance in humans

Abstract

Given the pivotal roles that CD4 T cell imbalance plays in human immune disorders, much interest centres on better understanding influences that regulate human helper T-cell subset dominance in vivo. Here, using primary CD4 T cells and short-term T helper type 1 (Th1) and Th2-like lines, we investigated roles and mechanisms by which neurotransmitter receptors may influence human type 1 versus type 2 immunity. We hypothesized that N-methyl-d-aspartate receptors (NMDA-R), which play key roles in memory and learning, can also regulate human CD4 T cell function through induction of excitotoxicity. Fresh primary CD4 T cells from healthy donors express functional NMDA-R that are strongly up-regulated upon T cell receptor (TCR) mediated activation. Synthetic and physiological NMDA-R agonists elicited Ca flux and led to marked inhibition of type 1 but not type 2 or interleukin-10 cytokine responses. Among CD4 lines, NMDA and quinolinic acid preferentially reduced cytokine production, Ca flux, proliferation and survival of Th1-like cells through increased induction of cell death whereas Th2-like cells were largely spared. Collectively, the findings demonstrate that (i) NMDA-R is rapidly up-regulated upon CD4 T cell activation in humans and (ii) Th1 versus Th2 cell functions such as proliferation, cytokine production and cell survival are differentially affected by NMDA-R agonists. Differential cytokine production and proliferative capacity of Th1 versus Th2 cells is attributable in part to increased physiological cell death among fully committed Th1 versus Th2 cells, leading to increased Th2-like dominance. Hence, excitotoxicity, beyond its roles in neuronal plasticity, may contribute to ongoing modulation of human T cell responses.

Critical Neurotransmitters in the Neuroimmune Network

“…Naïve T cells constitutively express GluA3 and mGluR 5 receptors (88, 261) Activated T cells express mGluR 1/5 and NMDAR GluN1 and/or GluN2B subunits (253) NMDARs are upregulated on activated T cells to compensate for GluA3 downregulation due to autocrine/paracrine granzyme B-mediated proteolytic cleavage (262) GluN1 is upregulated on CD4 + T cells, and leads to T H1 cell death and prevalence of T H2 responses (263) iGluR mediates Ca 2+ influx through a voltage-gated K + channel K v 1.3 (264), and increases IL-2 secretion and IL-2 receptor in T cells (265,266) mGluR activation increases Ca 2+ influx in T cells (266,267) support early events of TCR signaling through Glu-activated K v 1.3 K + channels, mGluR signaling sustains T cell activation and survival. Naïve T cells constitutively express GluA3 and mGluR 5 (88,261).…”

“…GluR signaling can contribute to immunosuppression. GluN1 is rapidly upregulated on CD4 + T cells, and leads to T H1 cell death and prevalence of T H2 responses in humans, interfering with the resolution chronic inflammatory diseases ( 263 ). DC-derived Glu stimulating the constitutively expressed mGluR 5 on T cells blocks their activation.…”

Interaction of neurotransmitters and neurochemicals with lymphocytes

“…Glutamate transporters, and receptors including metabotropic receptors mGluR1 and mGluR5, ionotropic receptors AMPA and kainate, are also expressed on immune cells including lymphocytes (Boldyrev et al, 2012;Ganor and Levite, 2014;Lujan et al, 1996;Meldrum, 2000;Vladychenskaya et al, 2011;Xue and Field, 2011). NMDA receptors are also found on lymphocytes and upregulated after lymphocyte activation (Orihara et al, 2018).…”

“…Glutamate enhances chemotactic migration of normal naive T cells towards CXCL12 (Ganor et al, 2003), stimulates AMPA receptors on T cells leading to activation, and triggers integrin-dependent adhesion of T cells to laminin and fibronectin (Ganor et al, 2003). NMDA receptor agonists increase T H 2 cell activity (Orihara et al, 2018). Glutamate promotes T cell proliferation in response to myelin oligodendrocyte glycoprotein and myelin basic protein, which are antigens implicated in multiple sclerosis (Koehler et al, 2002).…”

Autoantibodies against N-methyl-d-aspartate receptor 1 in health and disease

“…In the context of natural as well as pathological NMDAR1-AB, the emerging role of NMDAR in the immune system itself is intriguing: NMDAR antagonists dampen B cell [ 51 ] as well as T-cell functions [ 52 ]. NMDAR is rapidly upregulated upon CD4+ T-cell activation in humans and neurotransmitter/agonist signaling via NMDAR leads to decreased T helper type 1-like and enhanced T helper type 2-like immune balance, affecting proliferation, cytokine production and cell survival [ 53 ▪▪ ]. Even though ultimate proof of NMDAR1 functionality on blood cells is still pending, it is intriguing to speculate that NMDAR1-AB as humoral (auto)immunity players could feedback-modulate the immune system.…”