Dopamine, through the extracellular signal-regulated kinase pathway, downregulates CD4+CD25+ regulatory T-cell activity: implications for neurodegeneration.
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).
Kipnis
Jonathan
J
Department of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Cardon
Michal
M
Avidan
Hila
H
Lewitus
Gil M
GM
Mordechay
Sharon
S
Rolls
Asya
A
Shani
Yael
Y
Schwartz
Michal
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018698:Glutamic Acid; D007108:Immune Tolerance / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009409:Nerve Crush; D009410:Nerve Degeneration / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D020221:Optic Nerve Injuries / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D050641:Receptors, Dopamine D5; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D018491:Dopamine Agonists; C493606:Drd5 protein, mouse; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D017447:Receptors, Dopamine D1; D015375:Receptors, Interleukin-2; D050641:Receptors, Dopamine D5; D018698:Glutamic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine