Suppressing the Suppressors

Abstract

Although autoimmune responses are generally thought of as harmful, some research suggests that immunological activity directed against self-antigens exposed following damage to the central nervous system (CNS) might actually protect neurons adjacent to the injury site from secondary neurodegeneration. However, CD4 + CD25 + regulatory T cells (T reg ) generally suppress such autoimmune activity. Kipnis et al . investigated the effects of various neuronal messengers on mouse T reg activity and found that exposure of T reg to dopamine inhibited their ability to suppress the proliferation of cocultured effector T cells. In contrast, norepinephrine, serotonin, and substance P had no such effect. Pharmacological analysis indicated that the suppressive effect of dopamine on T reg activity was mediated through D1 or D5 receptors or both and involved inhibition of a signaling pathway including the mitogen-activated protein kinases ERK1 and ERK2. Furthermore, dopamine, acting through the ERK1-ERK2 pathway, inhibited T reg adhesion to chondroitin sulfate proteoglycans (extracellular matrix proteins associated with tissue injury), decreased immunofluorescence of the hyaluronate receptor CD44, and attenuated T reg migration toward the chemokine CCL22. In a mouse model of CNS injury in which the authors had previously demonstrated deleterious effects of T reg (retinal neuron degeneration after crushing of the optic nerve), systemic injection of dopamine proved neuroprotective. In a second mouse model (retinal ganglion cell death after intraocular glutamate injection), systemic injection of dopamine enhanced neuronal survival in wild-type but not SCID (severe combined immunodeficient) mice, which lack functional T cells. In contrast, systemic injection of a dopamine antagonist potentiated glutamate neurotoxicity. Thus, the authors suggest that manipulation of dopamine signaling could provide one approach to modulating T reg activity for therapeutic purposes. J. Kipnis, M. Cardon, H. Avidan, G. M. Lewitus, S. Mordechay, A. Rolls, Y. Shani, M. Schwartz, Dopamine, through the extracellular signal-regulated kinase pathway, downregulates CD4 + CD25 + regulatory T-cell activity: Implications for neurodegeneration. J. Neurosci . 24 , 6133-6143 (2004). [Abstract] [Full Text]