{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T15:04:08Z","timestamp":1780499048738,"version":"3.54.1"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Intestinal intraepithelial lymphocytes (IELs) are a versatile population of immune cells with both effector and regulatory roles in gut immunity. Although this functional diversity is thought to arise from distinct IEL subpopulations, the heterogeneity of TCR\u03b1\u03b2<jats:sup>+<\/jats:sup> and TCR\u03b3\u03b4<jats:sup>+<\/jats:sup> IELs have not been well characterized. Using scRNAseq, we identified CD8\u03b1\u03b1<jats:sup>+<\/jats:sup> T cell subsets with memory-like (<jats:italic>Tcf7<\/jats:italic><jats:sup>+<\/jats:sup>) and effector-like (<jats:italic>Prdm1<\/jats:italic><jats:sup>+<\/jats:sup>) profiles in both TCR\u03b1\u03b2<jats:sup>+<\/jats:sup> and TCR\u03b3\u03b4<jats:sup>+<\/jats:sup> IELs. Using CD160 and CD122 as markers of memory-like and effector-like cells, respectively, we found that while effector-like cells dominated the small intestine, memory-like IELs were more prevalent in the large intestine, suggesting a functional specialization of immune responses along the gut. Further transcriptional analysis revealed shared profiles between TCR\u03b1\u03b2<jats:sup>+<\/jats:sup> and TCR\u03b3\u03b4<jats:sup>+<\/jats:sup> small intestinal IEL subsets, suggesting conserved functional roles across these populations. Finally, our analysis indicated that TCR\u03b1\u03b2<jats:sup>+<\/jats:sup> memory-like IELs arise from <jats:italic>Tcf7<jats:sup>+<\/jats:sup><\/jats:italic> double-negative (DN) precursors, and that effector-like IELs subsequently differentiate from the memory-like population. In contrast, TCR\u03b3\u03b4<jats:sup>+<\/jats:sup> IELs appear to originate from two distinct precursor populations, one expressing <jats:italic>Tcf7<\/jats:italic> and the other <jats:italic>Zeb2<\/jats:italic>, indicating the presence of parallel developmental pathways within this lineage. Overall, our findings reveal that both TCR\u03b1\u03b2<jats:sup>+<\/jats:sup> and TCR\u03b3\u03b4<jats:sup>+<\/jats:sup> cells contain memory-like and effector-like subsets, which may contribute to the functional heterogeneity of IELs.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1637209","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T05:24:26Z","timestamp":1754371466000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Heterogeneity of CD8\u03b1\u03b1 intraepithelial lymphocytes is transcriptionally conserved between TCR\u03b1\u03b2 and TCR\u03b3\u03b4 cell lineages"],"prefix":"10.3389","volume":"16","author":[{"given":"Kaito A.","family":"Hioki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueting","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam 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