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 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-beta 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-alpha or interferon-gamma. 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.
Cosentino
Marco
M
Department of Clinical Medicine, Section of Experimental and Clinical Pharmacology, Center for Research in Neuroscience, University of Insubria, Via Ottorino Rossi n. 9, 21100 Varese VA, Italy. marco.cosentino@uninsubria.it
Fietta
Anna Maria
AM
Ferrari
Marco
M
Rasini
Emanuela
E
Bombelli
Raffaella
R
Carcano
Elena
E
Saporiti
Federica
F
Meloni
Federica
F
Marino
Franca
F
Lecchini
Sergio
S
D019898:Autocrine Communication / Q000187:drug effects* / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D002395:Catecholamines / Q000378:metabolism*; D049109:Cell Proliferation; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D019899:Paracrine Communication / Q000187:drug effects* / Q000276:immunology; D010835:Phytohemagglutinins / Q000276:immunology / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000276:immunology; D012110:Reserpine / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis* / Q000276:immunology
D015704:CD4 Antigens; D002395:Catecholamines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase