{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T22:28:15Z","timestamp":1791066495043,"version":"4.1.0"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,5,31]]},"abstract":"<jats:p>\n                    The pathways for differentiation of human CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells into functionally distinct subsets of memory cells\n                    <jats:italic>in vivo<\/jats:italic>\n                    are unknown. The identification of these subsets and pathways has clear implications for the design of vaccines and immune-targeted therapies. Here, we show that populations of apparently na\u00efve CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells express the chemokine receptors CXCR3 or CCR4 and demonstrate patterns of gene expression and functional responses characteristic of memory cells. The proliferation history and T cell receptor repertoire of these chemokine-receptor\n                    <jats:sup>+<\/jats:sup>\n                    cells suggest that they are very early memory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells that have \u201crested down\u201d before acquiring the phenotypes described for \u201ccentral\u201d or \u201ceffector\u201d memory T cells. In addition, the chemokine-receptor\n                    <jats:sup>+<\/jats:sup>\n                    \u201cna\u00efve\u201d populations contain Th1 and Th2 cells, respectively, demonstrating that Th1\/Th2 differentiation can occur very early\n                    <jats:italic>in vivo<\/jats:italic>\n                    in the absence of markers conventionally associated with memory cells. We localized ligands for CXCR3 and CCR4 to separate foci in T cell zones of tonsil, suggesting that the chemokine-receptor\n                    <jats:sup>+<\/jats:sup>\n                    subsets may be recruited and contribute to segregated, polarized microenvironments within lymphoid organs. Importantly, our data suggest that CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells do not differentiate according to a simple schema from na\u00efve \u2192 CD45RO\n                    <jats:sup>+<\/jats:sup>\n                    noneffector\/central memory \u2192 effector\/effector memory cells. Rather, developmental pathways branch early on to yield effector\/memory populations that are highly heterogeneous and multifunctional and have the potential to become stable resting cells.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0409720102","type":"journal-article","created":{"date-parts":[[2005,5,19]],"date-time":"2005-05-19T20:25:44Z","timestamp":1116534344000},"page":"7916-7921","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":79,"title":["Characterization of subsets of CD4\n                    <sup>+<\/sup>\n                    memory T cells reveals early branched pathways of T cell differentiation in humans"],"prefix":"10.1073","volume":"102","author":[{"given":"Kaimei","family":"Song","sequence":"first","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald L.","family":"Rabin","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenna J.","family":"Hill","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"De Rosa","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P.","family":"Perfetto","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei H.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Foley","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey S.","family":"Reiner","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Mattapallil","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Douek","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Roederer","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua M.","family":"Farber","sequence":"additional","affiliation":[{"name":"Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2005,5,19]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri778"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni969"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/44385"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.22.012703.104702"},{"key":"e_1_3_2_5_2","first-page":"568","volume":"68","year":"2000","unstructured":"Yamamoto, J., Adachi, Y., Onoue, Y., Adachi, Y. 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