Plasma Membrane Calcium ATPase Regulates Stoichiometry of CD4⁺ T-Cell Compartments

Immune responses involve mobilization of T cells within naïve and memory compartments. Tightly regulated Ca²⁺ levels are essential for balanced immune outcomes. How Ca²⁺ contributes to regulating compartment stoichiometry is unknown. Here, we show that plasma membrane Ca²⁺ ATPase 4 (PMCA4) is differentially expressed in human CD4⁺ T compartments yielding distinct store operated Ca²⁺ entry (SOCE) profiles. Modulation of PMCA4 yielded a more prominent increase of SOCE in memory than in naïve CD4⁺ T cell. Interestingly, downregulation of PMCA4 reduced the effector compartment fraction and led to accumulation of cells in the naïve compartment. In silico analysis and chromatin immunoprecipitation point towards Ying Yang 1 (YY1) as a transcription factor regulating PMCA4 expression. Analyses of PMCA and YY1 expression patterns following activation and of PMCA promoter activity following downregulation of YY1 highlight repressive role of YY1 on PMCA expression. Our findings show that PMCA4 adapts Ca²⁺ levels to cellular requirements during effector and quiescent phases and thereby represent a potential target to intervene with the outcome of the immune response.