A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity

Medientyp: E-Artikel
Titel: A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity
Beteiligte: Zhou, Xiao; Friedmann, Kim S.; Lyrmann, Hélène; Zhou, Yan; Schoppmeyer, Rouven; Knörck, Arne; Mang, Sebastian; Hoxha, Cora; Angenendt, Adrian; Backes, Christian S.; Mangerich, Carmen; Zhao, Renping; Cappello, Sabrina; Schwär, Gertrud; Hässig, Carmen; Neef, Marc; Bufe, Bernd; Zufall, Frank; Kruse, Karsten; Niemeyer, Barbara A.; Lis, Annette; Qu, Bin; Kummerow, Carsten; Schwarz, Eva C.;
Erschienen: Wiley, 2018
Erschienen in: The Journal of Physiology
Sprache: Englisch
DOI: 10.1113/jp274964
ISSN: 0022-3751; 1469-7793
Schlagwörter: Physiology
Entstehung:
Anmerkungen:
Beschreibung: <jats:sec><jats:title>Key points</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item><jats:p>Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are required to eliminate cancer cells.</jats:p></jats:list-item> <jats:list-item><jats:p>We analysed the Ca<jats:sup>2+</jats:sup> dependence of CTL and NK cell cytotoxicity and found that in particular CTLs have a very low optimum of [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> (between 122 and 334 n<jats:sc>m</jats:sc>) and [Ca<jats:sup>2+</jats:sup>]<jats:sub>o</jats:sub> (between 23 and 625 μ<jats:sc>m</jats:sc>) for efficient cancer cell elimination, well below blood plasma Ca<jats:sup>2+</jats:sup> levels.</jats:p></jats:list-item> <jats:list-item><jats:p>As predicted from these results, partial down‐regulation of the Ca<jats:sup>2+</jats:sup> channel Orai1 in CTLs paradoxically increases perforin‐dependent cancer cell killing.</jats:p></jats:list-item> <jats:list-item><jats:p>Lytic granule release at the immune synapse between CTLs and cancer cells has a Ca<jats:sup>2+</jats:sup> optimum compatible with this low Ca<jats:sup>2+</jats:sup> optimum for efficient cancer cell killing, whereas the Ca<jats:sup>2+</jats:sup> optimum for CTL migration is slightly higher and proliferation increases monotonously with increasing [Ca<jats:sup>2+</jats:sup>]<jats:sub>o</jats:sub>.</jats:p></jats:list-item> <jats:list-item><jats:p>We propose that a partial inhibition of Ca<jats:sup>2+</jats:sup> signals by specific Orai1 blockers at submaximal concentrations could contribute to tumour elimination.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec><jats:sec><jats:title>Abstract</jats:title><jats:p>Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are required to protect the human body against cancer. Ca<jats:sup>2+</jats:sup> is a key metabolic factor for lymphocyte function and cancer homeostasis. We analysed the Ca<jats:sup>2+</jats:sup> dependence of CTL and NK cell cytotoxicity against cancer cells and found that CTLs have a bell‐shaped Ca<jats:sup>2+</jats:sup> dependence with an optimum for cancer cell elimination at rather low [Ca<jats:sup>2+</jats:sup>]<jats:sub>o</jats:sub> (23–625 μ<jats:sc>m</jats:sc>) and [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> (122–334 n<jats:sc>m</jats:sc>). This finding predicts that a partial inhibition of Orai1 should increase (rather than decrease) cytotoxicity of CTLs at [Ca<jats:sup>2+</jats:sup>]<jats:sub>o</jats:sub> higher than 625 μ<jats:sc>m</jats:sc>. We tested this hypothesis in CTLs and indeed found that partial down‐regulation of Orai1 by siRNA increases the efficiency of cancer cell killing. We found two mechanisms that may account for the Ca<jats:sup>2+</jats:sup> optimum of cancer cell killing: (1) migration velocity and persistence have a moderate optimum between 500 and 1000 μ<jats:sc>m</jats:sc> [Ca<jats:sup>2+</jats:sup>]<jats:sub>o</jats:sub> in CTLs, and (2) lytic granule release at the immune synapse between CTLs and cancer cells is increased at 146 μ<jats:sc>m</jats:sc> compared to 3 or 800 μ<jats:sc>m</jats:sc>, compatible with the Ca<jats:sup>2+</jats:sup> optimum for cancer cell killing. It has been demonstrated in many cancer cell types that Orai1‐dependent Ca<jats:sup>2+</jats:sup> signals enhance proliferation. We propose that a decrease of [Ca<jats:sup>2+</jats:sup>]<jats:sub>o</jats:sub> or partial inhibition of Orai1 activity by selective blockers in the tumour microenvironment could efficiently reduce cancer growth by simultaneously increasing CTL and NK cell cytotoxicity and decreasing cancer cell proliferation. <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/tjp12820-gra-0001-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text></jats:p></jats:sec>
Zugangsstatus: Freier Zugang

Nur in Feld suchen:

Zuletzt gesuchte Begriffe: