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The neurotransmitter dopamine counteracts T cell functions through its specific receptor subtype D5R but favors T cell proliferation and adhesion when acting on D3R. We found diminished mRNA and protein levels of D5R, but not of D3R, in peripheral blood mononuclear cells (PBMCs) from untreated multiple sclerosis (MS) patients. Dopamine reduced T cell proliferation, secretion of interferon-gamma (IFN-gamma), and production of matrix metalloproteinase-9 (MMP-9) mRNA in PBMCs from controls but not from MS patients. By contrast, reduced levels of D3R and renewed dopamine-associated regulatory functions were found in PBMCs from IFN-beta treated MS patients. Failure of the dopaminergic system of lymphocytes may lessen the threshold of T cell activation and sustain the pathogenic cascade of MS.