A novel form of immune signaling revealed by transmission of the inflammatory mediator serotonin between dendritic cells and T cells.
Adaptive immunity is triggered at the immune synapse, where peptide-major histocompatibility complexes and costimulatory molecules expressed by dendritic cells (DCs) are physically presented to T cells. Here we describe transmission of the inflammatory monoamine serotonin (5-hydroxytryptamine [5-HT]) between these cells. DCs take up 5-HT from the microenvironment and from activated T cells (that synthesize 5-HT) and this uptake is inhibited by the antidepressant, fluoxetine. Expression of 5-HT transporters (SERTs) is regulated by DC maturation, exposure to microbial stimuli, and physical interactions with T cells. Significantly, 5-HT sequestered by DCs is stored within LAMP-1+ vesicles and subsequently released via Ca2+-dependent exocytosis, which was confirmed by amperometric recordings. In turn, extracellular 5-HT can reduce T-cell levels of cAMP, a modulator of T-cell activation. Thus, through the uptake of 5-HT at sites of inflammation, and from activated T cells, DCs may shuttle 5-HT to naive T cells and thereby modulate T-cell proliferation and differentiation. These data constitute the first direct measurement of triggered exocytosis by DCs and reveal a new and rapid type of signaling that may be optimized by the intimate synaptic environment between DCs and T cells. Moreover, these results highlight an important role for 5-HT signaling in immune function and the potential consequences of commonly used drugs that target 5-HT uptake and release.
O'Connell
Peta J
PJ
Robarts Research Institute, London, ON, Canada.
Wang
Xiangbin
X
Leon-Ponte
Matilde
M
Griffiths
Corrie
C
Pingle
Sandeep C
SC
Ahern
Gerard P
GP
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005089:Exocytosis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D051379:Mice; D012701:Serotonin / Q000276:immunology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013570:Synaptic Membranes / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D022161:Transport Vesicles / Q000276:immunology
D052118:Lysosomal-Associated Membrane Protein 1; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin