Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop

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 constitu- tively express tyrosine hydroxylase (TH, EC 1.14.16.2), the rate-limiting enzyme in the synthesis of catecholamines, and contain substantial amounts of dopamine, norepi- nephrine, and epinephrine, which are re- leased upon treatment with reserpine. Cate- cholamine release results in reduced production of interleukin-10 and transform- ing growth factor-b by Tregs, and in down- regulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the produc- tion of tumor necrosis factor-a or inter- feron-g. Tregs and Teffs express on the cell membrane both D1-like and D2-like dopami- nergic receptors to a similar extent (12%- 29%of the cells).Catecholamine-dependent down-regulation of Tregs is, however, selec- tively reversed by pharmacological block- ade of dopaminergic D1-like receptors, which in Tregs only (and not in Teffs) are also expressed at the level ofmRNAand are functionally coupled to intracellular produc- tion of cAMP. These findings indicate that in human Tregs endogenous catecholamines subserve anautocrine/paracrine loopinvolv- ing dopaminergic pathways and resulting in down-regulation of Treg function.