{"doi":"10.3389/fimmu.2025.1637209","title":"Heterogeneity of CD8αα intraepithelial lymphocytes is transcriptionally conserved between TCRαβ and TCRγδ cell lineages","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 TCRαβ<jats:sup>+</jats:sup> and TCRγδ<jats:sup>+</jats:sup> IELs have not been well characterized. Using scRNAseq, we identified CD8αα<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 TCRαβ<jats:sup>+</jats:sup> and TCRγδ<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 TCRαβ<jats:sup>+</jats:sup> and TCRγδ<jats:sup>+</jats:sup> small intestinal IEL subsets, suggesting conserved functional roles across these populations. Finally, our analysis indicated that TCRαβ<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, TCRγδ<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 TCRαβ<jats:sup>+</jats:sup> and TCRγδ<jats:sup>+</jats:sup> cells contain memory-like and effector-like subsets, which may contribute to the functional heterogeneity of IELs.</jats:p>","journal":"Frontiers in Immunology","year":2025,"id":608898,"datarank":0.24348296792994298,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0020672810648279067,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0020672810648279067,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":4,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1040478,"name":"Xueting Liang","orcid":"0000-0001-8983-2118","position":1,"is_corresponding":false},{"id":1040477,"name":"Adam C. Lynch","orcid":"0009-0003-4518-4392","position":2,"is_corresponding":false},{"id":495260,"name":"Ravi Ranjan","orcid":"0000-0002-9524-0503","position":3,"is_corresponding":false},{"id":485099,"name":"Elena L. Pobezinskaya","orcid":"0000-0001-6408-8732","position":4,"is_corresponding":false},{"id":295928,"name":"Leonid A. Pobezinsky","orcid":"0000-0002-6115-3559","position":5,"is_corresponding":false},{"id":560757,"name":"Kaito A. Hioki","orcid":"0000-0003-0121-8899","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Heterogeneity of CD8αα intraepithelial lymphocytes is transcriptionally conserved between TCRαβ and TCRγδ cell lineages","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 TCRαβ<jats:sup>+</jats:sup> and TCRγδ<jats:sup>+</jats:sup> IELs have not been well characterized. Using scRNAseq, we identified CD8αα<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 TCRαβ<jats:sup>+</jats:sup> and TCRγδ<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 TCRαβ<jats:sup>+</jats:sup> and TCRγδ<jats:sup>+</jats:sup> small intestinal IEL subsets, suggesting conserved functional roles across these populations. Finally, our analysis indicated that TCRαβ<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, TCRγδ<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 TCRαβ<jats:sup>+</jats:sup> and TCRγδ<jats:sup>+</jats:sup> cells contain memory-like and effector-like subsets, which may contribute to the functional heterogeneity of IELs.</jats:p>","is_dataset_classified":null,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40837586","pmcid":"PMC12361183","openalex_id":"https://openalex.org/W4412998252","authors":[],"funders":[{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM108556","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R21 AI133041","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM135096","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI146188","title":null},{"funder_name":"National Institutes of Health","grant_id":"1R21AI133041-01A1","title":"Defining the role of let-7 miRNAs in the differentiation of exhausted and memory T cells"},{"funder_name":"National Institutes of Health","grant_id":"5R01AI146188-04","title":"Defining post-transcriptional mechanisms that control CD8 T cell longevity, proliferation and differentiation"}],"total_grants":6,"fwci":1.6082,"citation_percentile":0.84118904,"influential_citations":0,"citation_trend":[{"year":2025,"count":1},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1637209/pdf","host_type":"journal"},{"url":"https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1637209/pdf","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fimmu.2025.1637209/full","host_type":"publisher"},{"url":"https://doi.org/10.3389/fimmu.2025.1637209","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40837586","host_type":"repository"},{"url":"https://doaj.org/article/cb0c971d199f42d48961bed66196a9c3","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12361183","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12361183","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12361183?pdf=render","host_type":"Europe_PMC"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40837586/","host_type":""},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12361183/","host_type":""}],"fields_of_study":["Immune Cell Function and Interaction","T-cell and B-cell Immunology","Immunotherapy and Immune Responses","03 medical and health sciences","0302 clinical medicine"],"mesh_terms":["Intraepithelial Lymphocytes","Animals","Immunologic Memory","Intestinal Mucosa","Mice, Inbred C57BL","T-Lymphocyte Subsets","Receptors, Antigen, T-Cell, gamma-delta","Receptors, Antigen, T-Cell, alpha-beta","CD8 Antigens","Cell Lineage","Mice"],"keywords":["Intraepithelial lymphocyte","T-cell receptor","Biology","Effector","CD8","Population","Cell biology","T cell","Cytotoxic T cell","Immune system","Memory T cell","Immunology","Genetics","Medicine","Memory","Zeb2 Gene","Blimp1/prdm1","Tcf1/tcf7","Dn Iels","Iel - Intraepithelial Lymphocyte","Vg7","Receptors, Antigen, T-Cell, alpha-beta","CD8 Antigens","Receptors, Antigen, T-Cell, gamma-delta","RC581-607","Mice, Inbred C57BL","Mice","T-Lymphocyte Subsets","Animals","Cell Lineage","Immunologic diseases. 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