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However, the influence of distinct tissue environments on the differentiation and clonal selection of polyclonal T cells remains unclear, primarily because of the technical challenges in tracking these cells in vivo. To address this question, we generated Tracking Recently Activated Cell Kinetics (TRACK) mice, a dual-recombinase fate-mapping system that enables precise spatial and temporal labeling of recently activated CD4\u207a T cells. Using TRACK mice during influenza infection, we observed organ-specific clonal selection and transcriptional differentiation in the lungs, mediastinal lymph nodes (medLNs), and spleen. T cell receptor (TCR) sequencing revealed that local antigenic landscapes and clonal identity shape repertoire diversity, resulting in a low clonal overlap between tissues during acute infection. During the effector phase, spleen-derived CD4\u207a T cells preferentially adopted a stem-like migratory phenotype, whereas those activated in the medLNs predominantly differentiated into T follicular helper (Tfh) cells. Memory formation was associated with increased clonal overlap between lung and medLN-derived cells, whereas splenic clones retained a distinct repertoire. Additionally, memory CD4\u207a T cells displayed converging antigen specificity across tissues over time. These results highlight the tissue-dependent mechanisms driving clonal selection and functional specialization during infection and underscore how memory development facilitates clonal redistribution and functional convergence.<\/jats:p>","DOI":"10.1101\/2025.08.25.672130","type":"posted-content","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T03:40:11Z","timestamp":1756438811000},"source":"Crossref","is-referenced-by-count":1,"title":["Tissue-specific clonal selection and differentiation of CD4\u207a T cells during infection"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0864-6098","authenticated-orcid":false,"given":"Roham","family":"Parsa","sequence":"first","affiliation":[{"name":"Immune Cell Dynamics and Function, Biohub New York, New York, NY 10032, USA"},{"name":"Laboratory of Mucosal Immunology, Rockefeller University, New York, NY 10063, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helder","family":"Assis","sequence":"additional","affiliation":[{"name":"Laboratory of Mucosal Immunology, Rockefeller University, New York, NY 10063, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago B.R.","family":"de Castro","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Dynamics, Rockefeller University, New York, NY 10063, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella Lima","family":"dos Reis","sequence":"additional","affiliation":[{"name":"Laboratory of Mucosal Immunology, Rockefeller University, New York, NY 10063, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arpita","family":"Sushil","sequence":"additional","affiliation":[{"name":"Immune Cell Dynamics and Function, Biohub New York, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Hartweger","sequence":"additional","affiliation":[{"name":": Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10063, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina M.","family":"Bilate","sequence":"additional","affiliation":[{"name":"Laboratory of Mucosal Immunology, Rockefeller University, New York, NY 10063, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Mucida","sequence":"additional","affiliation":[{"name":"Laboratory of Mucosal Immunology, Rockefeller University, New York, NY 10063, USA"},{"name":"Howard Hughes Medical Institute, Rockefeller University, New York, NY 10063, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080523250759000_2025.08.25.672130v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.021"},{"key":"2026080523250759000_2025.08.25.672130v2.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053411"},{"key":"2026080523250759000_2025.08.25.672130v2.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.1178334"},{"key":"2026080523250759000_2025.08.25.672130v2.4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-030409-101212"},{"key":"2026080523250759000_2025.08.25.672130v2.5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032414-112056"},{"key":"2026080523250759000_2025.08.25.672130v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.36"},{"key":"2026080523250759000_2025.08.25.672130v2.7","doi-asserted-by":"publisher","DOI":"10.1038\/nature18848"},{"key":"2026080523250759000_2025.08.25.672130v2.8","doi-asserted-by":"crossref","unstructured":"Jenkins, M. 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