A complex of Neuroplastin and Plasma Membrane Ca(2+) ATPase controls T cell activation.

The outcome of T cell activation is determined by mechanisms that balance Ca(2+) influx and clearance. Here we report that murine CD4 T cells lacking Neuroplastin (Nptn (-/-)), an immunoglobulin superfamily protein, display elevated cytosolic Ca(2+) and impaired post-stimulation Ca(2+) clearance, along with increased nuclear levels of NFAT transcription factor and enhanced T cell receptor-induced cytokine production. On the molecular level, we identified plasma membrane Ca(2+) ATPases (PMCAs) as the main interaction partners of Neuroplastin. PMCA levels were reduced by over 70% in Nptn (-/-) T cells, suggesting an explanation for altered Ca(2+) handling. Supporting this, Ca(2+) extrusion was impaired while Ca(2+) levels in internal stores were increased. T cells heterozygous for PMCA1 mimicked the phenotype of Nptn (-/-) T cells. Consistent with sustained Ca(2+) levels, differentiation of Nptn (-/-) T helper cells was biased towards the Th1 versus Th2 subset. Our study thus establishes Neuroplastin-PMCA modules as important regulators of T cell activation.