Sci. STKE, 13 July 2004
IMMUNOLOGY Suppressing the Suppressors
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 (Treg) generally suppress such autoimmune activity. Kipnis et al. investigated the effects of various neuronal messengers on mouse Treg activity and found that exposure of Treg 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 Treg 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 Treg adhesion to chondroitin sulfate proteoglycans (extracellular matrix proteins associated with tissue injury), decreased immunofluorescence of the hyaluronate receptor CD44, and attenuated Treg migration toward the chemokine CCL22. In a mouse model of CNS injury in which the authors had previously demonstrated deleterious effects of Treg (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 Treg 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]
Citation: Suppressing the Suppressors. Sci. STKE 2004, tw249 (2004).
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