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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.
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Submitted January 6, 2006
Accepted September 4, 2006
Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop
Marco Cosentino*, Anna Maria Fietta, Marco Ferrari, Emanuela Rasini, Raffaella Bombelli, Elena Carcano, Federica Saporiti, Federica Meloni, Franca Marino, and Sergio Lecchini
Dept of Clinical Medicine, University of Insubria, Varese, Italy
Dept. of Hematological, Pneumological & Cardiovascular Sciences, University of Pavia, Pavia, Italy
Dept. of Hematological, Pneumological and Cardiovascular Sciences, University of Pavia, Pavia, Italy
* Corresponding author; email: marco.cosentino{at}uninsubria.it.
CD4+CD25+ regulatory T lymphocytes (Treg) are specialized T cells playing a key role in the control of immune homeostasis. Here we show that human Treg constitutively express tyrosine hydroxylase (TH, EC 1.14.16.2), 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- by Treg, and in down regulation of Treg-dependent inhibition of effector T lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor- or interferon- . Treg and Teff 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 Treg is however selectively reversed by pharmacological blockade of dopaminergic D1-like receptors, which in Treg only (and not in Teff) are expressed also at the level of mRNA and are functionally coupled to intracellular production of cAMP. These findings indicate that in human Treg endogenous catecholamines subserve an autocrine/paracrine loop involving dopaminergic pathways and resulting in down regulation of Treg function.
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