{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T20:10:12Z","timestamp":1790453412020,"version":"4.1.0"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:00:00Z","timestamp":1629936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>T cell stemness and exhaustion coexist as two key contrasting phenomena during chronic antigen stimulation, such as infection, transplant, cancer, and autoimmunity. T cell exhaustion refers to the progressive loss of effector function caused by chronic antigen exposure. Exhausted T (T<jats:sub>EX<\/jats:sub>) cells highly express multiple inhibitory receptors and exhibit severe defects in cell proliferation and cytokine production. The term T cell stemness describes the stem cell-like behaviors of T cells, including self-renewal, multipotency, and functional persistence. It is well accepted that na\u00efve and some memory T cell subsets have stem cell-like properties. When investigating the exhaustive differentiation of T cells in chronic infection and cancer, recent studies highlighted the stemness of \u201cprecursors of exhausted\u201d T (T<jats:sub>PEX<\/jats:sub>) cells prior to their terminal differentiation to T<jats:sub>EX<\/jats:sub> cells. Clinically successful checkpoint blockades for cancer treatment appear to invigorate antitumor T<jats:sub>PEX<\/jats:sub> cells but not T<jats:sub>EX<\/jats:sub> cells. Here we discuss the transcriptional and epigenetic regulations of T cell stemness and exhaustion, with a focus on how systems immunology was and will be utilized to define the molecular basis underlying the transition of T<jats:sub>PEX<\/jats:sub> to T<jats:sub>EX<\/jats:sub> cells. We suggest a \u201cstepwise model\u201d of T cell stemness and exhaustion, in which loss of stemness and exhaustion progression are gradual multi-step processes. We provide perspectives on the research needed to define T cell stemness and exhaustion in the transplantation setting, in which allogenic T cells are also chronically exposed to alloantigens. A better understanding of T cell stemness and exhaustion will shed light on developing novel strategies for immunotherapies.<\/jats:p>","DOI":"10.3389\/fimmu.2021.725618","type":"journal-article","created":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T00:05:31Z","timestamp":1630109131000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":38,"title":["Schr\u00f6dinger\u2019s T Cells: Molecular Insights Into Stemness and Exhaustion"],"prefix":"10.3389","volume":"12","author":[{"given":"Nancy 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