Ca2+ signals:
Molecular Mechanisms and Integrative Functions Collaborative Research Center 894

Project A1 - Markus Hoth

Ca2+-dependent CTL and NK cell cytotoxicity

Cytotoxic T lymphocytes (CTL) and Natural Killer (NK) cells form intimate contacts with tumor cells called immune synapse. They eliminate target cells mostly by two mechanisms: perforin and granzymes released from lytic granules and by Fas-ligand Fas-receptor interaction.

We have shown that human CTL and NK cells induce both, target cell apoptosis and necrosis. CTL and NK cells have a Ca2+optimum for efficient cytotoxicity and the apoptosis-to-necrosis ratio is Ca2+dependent. Based on preliminary data, we will finalize the molecular analysis of channels, transporters and other molecules potentially involved in Ca2+dependent cytotoxicity: Next to STIM-Orai, KCa3.1 and TRPV2 channels are promising candidates.

Additionally, we found a significant effect of ESyt1/2 (which regulate endoplasmic reticulum-plasma membrane (ER-PM) junction formation), on Ca2+dependent CTL cytotoxicity. Considering the importance of CTL and NK cells in cellular immune therapy, we will screen natural compounds for their ability to modulate Ca2+dependent cytotoxicity in a high-content screen together with Rolf Müller’s group (HIPS, Saarbrücken). A major goal of the new funding period is to understand the role of Ca2+in human cytotoxicity diseases.

We will focus on three aspects, the role of Ca2+during a cytokine storm following the blockade of CTL and/or NK cell cytotoxicity, the role of Ca2+for interdependent CTL and NK cytotoxicity against human melanoma and potentially altered Ca2+dependent cytotoxicity of CTL and NK cells from patients with B-cell Non-Hodgkin lymphoma in cooperation with Stephan Stilgenbauer (Internal Medicine, Homburg).