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Despite their critical roles in vaccination and autoimmunity, the gene expression programs that define functionally distinct human Tfh states\u2014 and the molecular pathways engaged by Tfh positioned within the GC niche\u2014remain incompletely understood. This gap has limited translational efforts to monitor or therapeutically target specific Tfh states for clinical benefit. Here, we delineate human CD4 T cell heterogeneity in tonsils and peripheral blood using trimodal single-cell sequencing and spectral flow cytometry to define epigenomic, transcriptional, and proteomic features of distinct Tfh states. Tfh with a GC-like phenotype exhibited markedly increased chromatin accessibility and both mRNA and protein expression of G protein subunit gamma 4 (\n                  <jats:italic>GNG4)<\/jats:italic>\n                  . In tonsil, single-cell spatial transcriptomics defined\n                  <jats:italic>GNG4<\/jats:italic>\n                  expression as a distinguishing feature of activated Tfh states within spatially demarcated GC compartments, with greater specificity than conventionally GC-associated features such as\n                  <jats:italic>BCL6, TOX2,<\/jats:italic>\n                  and\n                  <jats:italic>S1PR2<\/jats:italic>\n                  . In contrast,\n                  <jats:italic>GNG4<\/jats:italic>\n                  <jats:sup>\u2212<\/jats:sup>\n                  Tfh primarily localized to nonGC regions and exhibited a resting, Th17-polarized phenotype. Together, these data highlight\n                  <jats:italic>GNG4<\/jats:italic>\n                  as a central feature of activated, GC-positioned Tfh cell identity in humans.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    <jats:italic>GNG4<\/jats:italic>\n                    expression defines activated CD4 T follicular helper cells localized to the germinal center of human lymphoid tissue.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.10.693235","type":"posted-content","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T22:40:13Z","timestamp":1765665613000},"source":"Crossref","is-referenced-by-count":2,"title":["Multimodal analysis defines\n                  <i>GNG4<\/i>\n                  as a distinguishing feature of germinal center-positioned CD4 T follicular helper cells in humans"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9799-8089","authenticated-orcid":false,"given":"Sam Barnett","family":"Dubensky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4783-3515","authenticated-orcid":false,"given":"Yutong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7713-1779","authenticated-orcid":false,"given":"Kingsley 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Luna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9214-659X","authenticated-orcid":false,"given":"Katherine","family":"Premo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7994-1219","authenticated-orcid":false,"given":"Yi","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7294-8683","authenticated-orcid":false,"given":"Suzanna","family":"Rachimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emylette Cruz","family":"Cabrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7158-9760","authenticated-orcid":false,"given":"Bria","family":"Fulmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9704-3127","authenticated-orcid":false,"given":"Ijeoma C.","family":"Meremikwu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5569-4132","authenticated-orcid":false,"given":"Sarah 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