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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3139-3146.
Prepublished online as a Blood First Edition Paper on December 14, 2006December 7, 2006; DOI 10.1182/blood-2006-10-052787.


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Submitted October 18, 2006
Accepted November 28, 2006

Serotonin provides an accessory signal to enhance T cell activation by signaling through the 5-HT7 receptor

Matilde Leon-Ponte, Gerard P Ahern, and Peta J O'Connell*

Departments of Surgery, Microbiology and Immunology, Robarts Research Institute, University of Western Ontario, Ontario, Canada
Department of Pharmacology, Georgetown University, Washington, DC, United States

* Corresponding author; email: peta{at}robarts.ca.

Although typically considered a neurotransmitter, there is substantial evidence that serotonin (5-HT) plays an important role in the pathogenesis of inflammatory disorders. Despite these findings, the precise role of 5-HT in modulating immune function, particularly T cell function, remains elusive. We report that naive T cells predominantly express the type 7 5-HT receptor (5-HTR) and expression of this protein is substantially enhanced upon T cell activation. In addition, T cell activation leads to expression of the 5-HT1B and 5-HT2A receptors. Significantly, exogenous 5-HT induces rapid phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and I{kappa}B{alpha} in naive T cells. 5-HT-induced activation of ERK 1/2 and NF{kappa}B is inhibited by preincubation with a specific 5-HT7 receptor antagonist. Thus, 5-HT signaling via the 5-HT7 receptor may contribute to early T cell activation. In turn, 5-HT synthesized by T cells may act as autocrine factor. Consistent with this hypothesis, we found that inhibition of 5-HT synthesis with parachlorophenylalanine (PCPA) impairs T cell activation and proliferation. Combined, these data demonstrate a fundamental role for 5-HT as an intrinsic co-factor in T cell activation and function, and suggest an alternative mechanism through which immune function is regulated by indoleamine 2,3-dioxygenase-mediated catabolism of tryptophan.


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