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The Journal of Neuroscience, July 7, 2004, 24(27):6133-6143; doi:10.1523/JNEUROSCI.0600-04.2004

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Development/Plasticity/Repair
Dopamine, through the Extracellular Signal-Regulated Kinase Pathway, Downregulates CD4⁺CD25⁺ Regulatory T-Cell Activity: Implications for Neurodegeneration

Jonathan Kipnis, Michal Cardon, Hila Avidan, Gil M. Lewitus, Sharon Mordechay, Asya Rolls, Yael Shani, and Michal Schwartz

Department of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel

Fighting off neuronal degeneration requires a well controlled T-cell response against self-antigens residing in sites of the CNS damage. The ability to evoke this response is normally suppressed by naturally occurring CD4⁺CD25⁺ regulatory T-cells (Treg). No physiological compound that controls Treg activity has yet been identified. Here, we show that dopamine, acting via type 1 dopamine receptors (found here to be preferentially expressed by Treg), reduces the suppressive activity and the adhesive and migratory abilities of Treg. Treg activity was correlated with activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) signaling pathway. Systemic injection of dopamine or an agonist of its type 1 receptors significantly enhanced, via a T-cell-dependent mechanism, protection against neuronal death after CNS mechanical and biochemical injury. These findings shed light on the physiological mechanisms controlling Treg and might open the way to novel therapeutic strategies for downregulating Treg activity (e.g., in neuronal degeneration) or for strengthening it (in autoimmune diseases).

Key words: CD4⁺CD25⁺ regulatory T-cells; neurotransmitters; dopamine; dopamine receptors; ERK1/2; autoimmune response; neuroprotection; neurodegeneration; CNS

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Received Feb 19, 2004; revised May 28, 2004; accepted May 28, 2004.

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