Research ArticleCalcium signaling

Frontrunners of T cell activation: Initial, localized Ca2+ signals mediated by NAADP and the type 1 ryanodine receptor

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Science Signaling  13 Oct 2015:
Vol. 8, Issue 398, pp. ra102
DOI: 10.1126/scisignal.aab0863

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Calcium signals down to the millisecond

Engagement of the T cell receptor (TCR) stimulates Ca2+ signaling, which is required for T cell activation. The earliest Ca2+ signals are short-lived and localized near the sites of TCR stimulation; later events are longer-lasting and more widespread. Wolf et al. used a combination of fluorescent indicator dyes and microscopy to perform high-resolution imaging of Ca2+ signals that occurred within milliseconds of the TCR stimulation of live mouse and human T cells. Microinjection of cells with the second messenger NAADP, which is generated upon T cell activation, produced a similar spatiotemporal pattern of Ca2+ signals in the absence of TCR activation. Both TCR- and NAADP-dependent signals were markedly reduced by depletion of ryanodine receptors, which are localized in the endoplasmic reticulum, implicating this internal calcium store as a source for the early Ca2+ signals required for T cell activation.


The activation of T cells is the fundamental on switch for the adaptive immune system. Ca2+ signaling is essential for T cell activation and starts as initial, short-lived, localized Ca2+ signals. The second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) forms rapidly upon T cell activation and stimulates early Ca2+ signaling. We developed a high-resolution imaging technique using multiple fluorescent Ca2+ indicator dyes to characterize these early signaling events and investigate the channels involved in NAADP-dependent Ca2+ signals. In the first seconds of activation of either primary murine T cells or human Jurkat cells with beads coated with an antibody against CD3, we detected Ca2+ signals with diameters close to the limit of detection and that were close to the activation site at the plasma membrane. In Jurkat cells in which the ryanodine receptor (RyR) was knocked down or in primary T cells from RyR1−/− mice, either these early Ca2+ signals were not detected or the number of signals was markedly reduced. Local Ca2+ signals observed within 20 ms upon microinjection of Jurkat cells with NAADP were also sensitive to RyR knockdown. In contrast, TRPM2 (transient receptor potential channel, subtype melastatin 2), a potential NAADP target channel, was not required for the formation of initial Ca2+ signals in primary T cells. Thus, through our high-resolution imaging method, we characterized early Ca2+ release events in T cells and obtained evidence for the involvement of RyR and NAADP in such signals.

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