Immune responses involve mobilization of T cells within naïve and memory compartments. Tightly regulated Ca 2+ levels are essential for balanced immune outcomes. How Ca 2+ contributes to regulating compartment stoichiometry is unknown. Here, we show that plasma membrane Ca 2+ ATPase 4 (PMCA4) is differentially expressed in human CD4 + T compartments yielding distinct store operated Ca 2+ entry (SOCE) profiles. Modulation of PMCA4 yielded a more prominent increase of SOCE in memory than in naïve

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... 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 Ca 2+ levels to cellular requirements during effector and quiescent phases and thereby represent a potential target to intervene with the outcome of the immune response. A 5,000 bp long sequence upstream to start codon of ATP2B4 was used as a potential promoter sequence for ATP2B4. Merino-Wong et al. PMCA and YY1 Regulate CD4+ Compartments Frontiers in Immunology | www.frontiersin.org May 2021 | Volume 12 | Article 687242