A complex of Neuroplastin and Plasma Membrane Ca2+ ATPase controls T cell activation

The outcome of T cell activation is determined by mechanisms that balance CA²⁺ influx and clearance. Here we report that murine CD4 T cells lacking Neuroplastin (Nptn ^-/-), an immunoglobulin superfamily protein, display elevated cytosolic CA²⁺ and impaired post-stimulation CA²⁺ 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 CA²⁺ 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 CA²⁺ handling. Supporting this, CA²⁺ extrusion was impaired while CA²⁺ levels in internal stores were increased. T cells heterozygous for PMCA1 mimicked the phenotype of Nptn ^-/- T cells. Consistent with sustained CA²⁺ 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.