Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

A cytotoxic T lymphocyte (CTL) kills an infected or tumorigenic cell by Ca 2+ -dependent exocytosis of cytolytic granules at the immunological synapse formed between the two cells. Although inositol 1,4,5-trisphosphate (IP 3 )-mediated Ca 2+ release from the endoplasmic reticulum activates the store-operated Ca 2+ -influx pathway that is necessary for exocytosis, it is not a sufficient stimulus [1-4]. Here we identify the Ca 2+ -mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and its recently identified molecular target, two-pore channels (TPCs) [5-7], as being important for T cell receptor signaling in CTLs. We demonstrate that cytolytic granules are not only reservoirs of cytolytic proteins but are also the acidic Ca 2+ stores mobilized by NAADP via TPC channels on the granules themselves, so that TPCs migrate to the immunological synapse upon CTL activation. Moreover, NAADP activates TPCs to drive exocytosis in a way that is not mimicked by global Ca 2+ signals induced by IP 3 or ionomycin, suggesting that critical, local Ca 2+ nanodomains around TPCs stimulate granule exocytosis. Hence, by virtue of the NAADP/TPC pathway, cytolytic granules generate Ca 2+ signals that lead to their own exocytosis and to cell killing. This study highlights a selective role for NAADP in stimulating exocytosis crucial for immune cell function and may impact on stimulus-secretion coupling in wider cellular contexts. © 2012 Elsevier Ltd.

Original publication

DOI

10.1016/j.cub.2012.10.035

Type

Journal article

Journal

Current Biology

Publication Date

18/12/2012

Volume

22

Pages

2331 - 2337