{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T20:03:51Z","timestamp":1784318631559,"version":"3.55.0"},"posted":{"date-parts":[[2026,6,26]]},"group-title":"In Review","reference-count":0,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,21]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  Memory T cells are critical for vaccines and T-cell-based therapies. However, the differentiation path of memory T cells is not completely understood. Early bulk cell population-based studies support a linear model, in which effector T cells lose the effector program and dedifferentiate into memory T cells. Recent research supports a bifurcation model, where T cells choose one of the two paths, either the effector or the memory path, at an early stage of T cell responses. Terminal effector T cells lose the capacity to become memory T cells. Here, we first demonstrate that the expression of granzyme A is largely distinct from that of granzyme B and marks terminal cytotoxic effector CD8\n                  <sup>+<\/sup>\n                  T cells with reduced polyfunctionality. Using a granzyme A-fate mapping mouse line and an acute viral infection model, we discovered that early memory T cells are largely derived from cells lacking a history of granzyme A expression, supporting the bifurcation model. Progressively, granzyme A-expressing terminal effector T cells dedifferentiate into functional long-term memory T cells. At the late memory phase, memory T cells are a mixed population composed of cells with different differentiation paths (i.e., the linear and the bifurcated paths) that coordinate to provide balanced immune protection.\n                <\/p>","DOI":"10.21203\/rs.3.rs-10107441\/v1","type":"posted-content","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T15:46:06Z","timestamp":1782488766000},"source":"Crossref","is-referenced-by-count":0,"title":["Granzyme A-expressing Terminal Effector T Cells Dedifferentiate into Long-lived Memory T Cells"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9695-210X","authenticated-orcid":false,"given":"Nu","family":"Zhang","sequence":"first","affiliation":[{"name":"University of Texas Health Science Center at San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyu","family":"Ma","sequence":"additional","affiliation":[{"name":"The University of Texas Health Science Center at San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hunan Children\u2019s Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saranya","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"University of Texas Health San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhui","family":"he","sequence":"additional","affiliation":[{"name":"University of Texas Health San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Fan","sequence":"additional","affiliation":[{"name":"University of Texas Health San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyng-An","family":"Zhou","sequence":"additional","affiliation":[{"name":"University of Texas Health San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Segura-Cepero","sequence":"additional","affiliation":[{"name":"University of Texas Health San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heetanshi","family":"Jain","sequence":"additional","affiliation":[{"name":"University of Texas Health San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahana","family":"Jayakumar","sequence":"additional","affiliation":[{"name":"University of Texas Health San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1562-9218","authenticated-orcid":false,"given":"Weiguo","family":"Cui","sequence":"additional","affiliation":[{"name":"Northwestern University Feinberg School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Luan","sequence":"additional","affiliation":[{"name":"University of Texas Health San Antonio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-10107441\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-10107441\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T19:40:36Z","timestamp":1784317236000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-10107441\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":0,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-10107441\/v1","relation":{},"subject":[],"published":{"date-parts":[[2026,6,26]]},"subtype":"preprint"}}