T Lymphocyte Integrated Endoplasmic Reticulum Ca Store Signaling Functions Are Linked to Sarco/Endoplasmic Reticulum Ca-ATPase Isoform-Specific Levels of Regulation.

We explored the effects of altering expression levels of the sarco/endoplasmic reticulum Ca-ATPase (SERCA) ion-transporting enzymes on key T lymphocyte signaling functions. In these studies, we have taken advantage of the Jurkat T cell line which provides a T lymphocyte model cell phenotype with a well-characterized T cell receptor (TCR)-activated signaling pathway, as well as offering a cellular system with a good understanding of the SERCA expression profile. These studies have been prompted by a strong imperative to gain a better understanding of the complex roles SERCA Ca pumps play in the integrated TCR-activated signaling network, particularly given the central role of SERCA functions in regulating essential endoplasmic reticulum (ER) integrity. We find in this study that altering SERCA expression can significantly reconfigure ER Ca stores, increasing or decreasing Ca storage capacity depending on upregulation or downregulation of SERCA expression, and these effects are also associated with substantial changes in agonist-induced Ca release and influx patterns. Not surprisingly, these fundamental changes in TCR-regulated Ca signaling properties are associated with major alterations in T lymphocyte functions including regulation of growth patterns, cytokine secretion and energy utilization. Our study also describes additional evidence revealing intriguing functional distinctions between the major SERCA isoform-regulated Ca stores in T lymphocytes. Our work thus serves to reinforce increasing efforts to target the SERCA pumps as a potential profitable strategy to produce novel engineered T lymphocytes in the rapidly growing field of T-cell immunotherapy.