Proceedings of The Physiological Society

University College Dublin (2009) Proc Physiol Soc 15, SA28

Research Symposium

How mitochondria and ROS control calcium dependent T-cell activation

A. Quintana1, I. Bogeski1, C. Kummerow1, D. Al-Ansary1, C. Junker1, M. Pasche2, U. Becherer2, J. Rettig2, B. A. Niemeyer1, E. C. Schwarz1, M. Hoth1

1. Biophysics, Saarland University, Homburg, Germany. 2. Physiology, Saarland University, Homburg, Germany.

T-cell activation is required for the adaptive immune response. Formation of the immunological synapse (IS) between T-cells and antigen-presenting cells provides a highly-organized molecular mechanism to integrate cell surface events into T-cell activation. Calcium influx through CRAC/ORAI1 channels at the IS is necessary for T-cell activation. We show that formation of the IS induced cytoskeleton-dependent mitochondrial re-distribution to the immediate vicinity of the IS. Using total internal reflection microscopy, we found that upon stimulation the distance between the IS and mitochondria was decreased to values smaller than 200 nm. Consequently, mitochondria close to the IS took up more calcium than the ones further away from the IS. The re-distribution of mitochondria to the IS decreased the calcium microdomain at the IS and was necessary to maintain calcium influx through CRAC/ORAI1 channels by inhibiting their calcium dependent inactivation. Reactive oxygen species (ROS), which among other sources are generated by mitochondria, were found to inhibit CRAC/ORAI1 channels through cysteine oxidation adding a negative feedback inhibition of calcium entry by mitochondria. The intimate contact between mitochondria and the plasma membrane at the IS thus controls T-cell activation in a calcium and ROS dependent manner.

Where applicable, experiments conform with Society ethical requirements