{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T09:17:00Z","timestamp":1783329420019,"version":"3.54.6"},"reference-count":116,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>T cells are the central regulators of the adaptive immune system, guiding both the cell-mediated and antibody-based elements of the immune response. Crucial to T-cell activation and differentiation, the T-cell receptor must transduce antigen exposure using a sustained elevated Ca2+ signal. A substantial body of research has identified and characterized multiple players in the Ca2+ signaling pathway, yet the sarcoplasmic\/endoplasmic reticulum Ca2+-ATPase (SERCA) transporters, which intervene actively to regulate Ca2+ signal patterning and duration, remain relatively poorly characterized in the full scope of the T-cell signaling paradigm. In this review, we summarize the expanding research that is beginning to clarify the multiple complex roles SERCAs perform in shaping the information-rich Ca2+ signal. Pharmacologic modulators and other studies have revealed molecular and functional diversity in the SERCA pumps, with increasing recognition of their critical positioning in regulating ER Ca2+ store networks and functional roles, which ultimately derive from dynamic microdomain assemblies containing potentially highly tailored SERCA-binding protein interactomes. A better understanding of SERCA transporter functions underlies increasing interest in developing novel therapeutic strategies targeting these key ion pumps in efforts to engineer T-cell phenotypes for more therapeutically efficacious management of cancer, autoimmunity, and other immune-based pathologies.<\/jats:p>","DOI":"10.3390\/cells15131221","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T08:05:38Z","timestamp":1783325138000},"page":"1221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Guardians of T-Cell Ca2+ Stores: SERCA Pumps Integrated Within Complex Functional and Disease-State Signaling Dynamics"],"prefix":"10.3390","volume":"15","author":[{"given":"MD Nasim","family":"Uddin","sequence":"first","affiliation":[{"name":"Department of Cell and Biological Systems, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1146\/annurev.immunol.19.1.497","article-title":"Calcium signaling mechanisms in T lymphocytes","volume":"19","author":"Lewis","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1146\/annurev.ph.52.030190.002215","article-title":"Ion channels and signal transduction in lymphocytes","volume":"52","author":"Lewis","year":"1990","journal-title":"Annu. Rev. 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