Calcium regulation in the immune system

A multi-step process regulates the amount of calcium in the cytoplasm of non-excitable cells including T cells of the immune system. Only three different types of channels for calcium entry through the T cell plasma membrane after activation have been described so far. The EU-funded CAV IN IMMUNE SYSTEM (Molecular mechanism of calcium entry in the immune system) project investigated the existence of a new route for calcium entry.

Results revealed that calcium entry during an immune response consisted of L type voltage-gated calcium channels (Cavs) and their regulatory scaffold protein AHNAK1. The researchers focused on the role of the Cav/AHNAK pathway during an immune response. Which includes proliferation, migration and cytokine production. They found that both chemokine stimulation and T cell receptor (TCR) activation increased AHNAK1 protein expression in T cells.

As a next step scientists investigated the localisation of AHNAK1 in T cells. They showed that AHNAK1 is located in closely-packed vesicles in naïve T cells. Moreover, short term stimulation through TCR caused AHNAK1 to relocate to the cytoplasm or membranes. SDF-1 stimulation also had similar effects on AHNAK1 localisation.

Inhibition of AHNAK1 protein expression in Jurkat T cells by small hairpin RNA reduced cell migration to SDF-1. Taken together, the results suggest that the AHNAK1 protein is essential for calcium entry after SDF-1 stimulation.

Researchers stimulated TCR cells and observed the effect of knockdown and over-expression of cloned T cell Cav1.1 in 293HEK cells as they lack TCR. Results suggested that TCR signalling controls the gating of Cav1.1 channels through modified voltage dependence.

Overall, CAV IN IMMUNE SYSTEM study outcomes indicate that AHNAK1 and Cav1.1 are used for calcium entry during activation, adhesion and migration of T cells. This data has been summarised in two manuscripts for publication.

Study data could be applied to resolve immune system deficiency diseases. Furthermore, it is also possible that tumour cells, originating from the immune system or other non-excitable cells, use this mechanism for tumour development and metastasis. This has significant implications in biomedicine.