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.