Amazing stuff!
"... New research by immunologists in Germany is shedding light on how that amplification occurs in T cells, revealing a key molecular mechanism that helps trigger immune responses—and may also contribute to inflammatory conditions. ...
identified a crucial step in the production of a "second messenger," an internal signal that relays and amplifies messages received at the cell surface. Because external signaling molecules cannot enter the cell, second messengers translate those cues into powerful intracellular responses.
In T cells, that process depends on NAADP (nicotinic acid adenine dinucleotide phosphate), a molecule that drives calcium (Ca²⁺) signaling—an essential step in T cell activation. Without it, T cells cannot become the effector cells needed to fight serious threats, such as infections or cancer.
"T cell activation critically depends on the calcium ion (Ca²⁺)–mobilizing second messenger NAADP," ... "NAADP induces localized Ca²⁺ signals that expand into global cellular responses." ...
identified critical signaling events that induce the generation of a calcium-mobilizing second messenger in a study involving a human T cell line and another line of mouse T cells. ...
The team found that NAADP is produced at the immunological synapse—the contact point between T cells and other cells, such as antigen-presenting dendritic cells, by the enzyme DUOX2. But fully activating DUOX2 requires more than a simple trigger.
Instead, the researchers discovered that multiple signaling pathways converge to switch the enzyme on. One pathway involves PKCθ, activated downstream of the T cell receptor at the synapse. Another involves protein kinase A (PKA), activated through adenosine A2A receptors at sites away from the synapse.
Together, these pathways modify DUOX2 through phosphorylation, enabling it to generate sufficient NAADP to drive calcium signaling. ..."
From the significance and abstract:
"Editor’s summary
Generation of the second messenger NAADP by the enzyme DUOX2 induces the formation of Ca2+ hotspots that ultimately lead to T cell activation.
Winterberg et al. sought to understand how NAADP synthesis by DUOX2 is stimulated during T cell activation. DUOX2 was activated by Ca2+ itself. However, the phosphorylation of the same residue in DUOX2 by the protein kinases PKA Cβ2 and PKCθ was necessary for the full NAADP-synthesizing activity of DUOX2 in T cells. Whereas PKA Cβ2 was activated downstream of adenosine A2A receptors, PKCθ was activated downstream of the T cell receptor. These results suggest that NAADP production by DUOX2 is regulated by the integration of signals from the T cell receptor and other pathways during T cell activation. ...
Abstract
T cell activation critically depends on the calcium ion (Ca2+)–mobilizing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate), which induces the formation of Ca2+ microdomains that initiate global Ca2+ signals. NAADP is produced in immune synapses in T cells by dual NADPH oxidase 2 (DUOX2). Here, we investigated the mechanisms that stimulate DUOX2 activity in T cells. DUOX2 activity was enhanced by a modest increase in intracellular Ca2+ concentration, similar to that induced by Ca2+ microdomains that arise in resting T cells through different T cell receptor (TCR)–independent mechanisms.
In addition, DUOX2 was activated in vitro by phosphorylation of threonine-789 mediated by PKA Cβ or PKCθ, and genetic deficiency of PKA Cβ2 or PKCθ decreased NAADP-dependent Ca2+ microdomain formation in T cells. PKA Cβ2 was activated downstream of adenosine A2A receptors, independently of the TCR. In contrast, PKCθ was activated by the tyrosine kinase LCK downstream of TCR stimulation. Inhibition of A2A receptors or PKCθ to prevent full DUOX2 activation decreased the production of the proinflammatory cytokine IL-17 by effector T cells.
Thus, full stimulation of NAADP signaling that is critical for T cell activation requires integration of multiple TCR-independent and -dependent signals with different spatiotemporal characteristics by DUOX2, a fine-tuning mechanism that could be relevant for inflammation."
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