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Blood, 15 January 2007, Vol. 109, No. 2, pp. 632-642. Prepublished online as a Blood First Edition Paper on September 19, 2006; DOI 10.1182/blood-2006-01-028423.
IMMUNOBIOLOGY Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop1 Department of Clinical Medicine, Section of Experimental and Clinical Pharmacology, 2 Center for Research in Neuroscience, University of Insubria, Varese, Italy; 3 Department of Hematological, Pneumological, and Cardiovascular Sciences, University of Pavia, Italy
CD4+CD25+ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the control of immune homeostasis. Here, we show that human Tregs constitutively express tyrosine hydroxylase (TH, EC 1.14.16.2
[EC]
), the rate-limiting enzyme in the synthesis of catecholamines, and contain substantial amounts of dopamine, norepinephrine, and epinephrine, which are released upon treatment with reserpine. Catecholamine release results in reduced production of interleukin-10 and transforming growth factor-ß by Tregs, and in down-regulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor-
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
or interferon-
. Tregs and Teffs express on the cell membrane both D1-like and D2-like dopaminergic receptors to a similar extent (12%-29% of the cells). Catecholamine-dependent down-regulation of Tregs is, however, selectively reversed by pharmacological blockade of dopaminergic D1-like receptors, which in Tregs only (and not in Teffs) are also expressed at the level of mRNA and are functionally coupled to intracellular production of cAMP. These findings indicate that in human Tregs endogenous catecholamines subserve an autocrine/paracrine loop involving dopaminergic pathways and resulting in down-regulation of Treg function. 
