Abstract:
Intracellular calcium in T cells is an important control mechanism for immune response. In particular, calcium oscillations activate T cells in the lungs which leads to excessive contraction of airway smooth muscle cells (ASMC) during asthma. T cells, therefore, play a vital role in the immune response during asthma. We evaluate the importance of endoplasmic reticulum (ER) depletion, store-operated calcium channels (SOCC) and the activation of the transcription factor, nuclear factor of activated T cell (NFAT) during an immune response by constructing a mathematical model of the signalling processes along the calcium pathway in T cells. The model of the calcium dynamics in T cells is based upon calcium-release activated calcium (CRAC) current, through ER depletion and SOCC. The NFAT cycle is regulated by calcium/calmodulin-dependent calcineurin. NFAT in resting cells is highly phosphorylated and requires calcineurin for dephosphorylation, nuclear translocation and efficient DNA transcription. Our model shows that SOCC is vital in maintaining intracellular calcium oscillations, an elevated intracellular calcium concentration, as well as the downstream activation of NFAT. The model shows that the frequency of calcium oscillations increases the efficiency of NFAT activation. The model, however, predicts that constant calcium is more efficient in regulating the NFAT cycle than oscillatory calcium. This disagrees with previous models of NFAT regulation, where NFAT is more efficiently regulated by oscillating calcium than constant calcium, particularly at low concentrations. Furthermore, the model shows that the down-regulation of SOCC terminates the activation of NFAT; and, thus the activation of the T cell.
