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Here, circulating CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells with high programmed cell death 1 (PD-1) and ICOS coexpression were temporally associated with onset of virus control, seroconversion, and hepatitis in HCV-infected chimpanzees. Coproduction of T follicular helper (Tfh) (IL-21 and CXCL13) and Th1 (IFN-\u03b3 and TNF) cytokines after stimulation with HCV nonstructural proteins demonstrated that the response was predominately Tfh1 like and virus specific. Transcriptional analysis verified a Tfh1 lineage assignment. Effector-related genes such as\n                    <jats:italic>ADGRG1<\/jats:italic>\n                    (GPR56),\n                    <jats:italic>ZNF683<\/jats:italic>\n                    (Hobit), and\n                    <jats:italic>KLRB1<\/jats:italic>\n                    (CD161) were also expressed. HCV-specific PD-1\n                    <jats:sup>hi<\/jats:sup>\n                    ICOS\n                    <jats:sup>hi<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    Tfh1-like cells were enriched in liver, suggesting the potential for B and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell help at the site of virus replication. Most circulating and intrahepatic PD-1\n                    <jats:sup>hi<\/jats:sup>\n                    ICOS\n                    <jats:sup>hi<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    Tfh1-like cells did not express CXCR5 and therefore resembled CXCR5\n                    <jats:sup>\u2013<\/jats:sup>\n                    CXCL13\n                    <jats:sup>+<\/jats:sup>\n                    peripheral helper cells that infiltrate tumors and tissues inflamed by autoimmunity. PD-1\n                    <jats:sup>hi<\/jats:sup>\n                    ICOS\n                    <jats:sup>hi<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    Tfh1-like cells also peaked after hepatitis A virus infection, but the response was accelerated by several weeks compared with HCV infection. The PD-1\n                    <jats:sup>hi<\/jats:sup>\n                    ICOS\n                    <jats:sup>hi<\/jats:sup>\n                    phenotype and temporal association between the peak response and alanine aminotransferase may provide markers to guide human studies of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell immunity against HCV and other hepatotropic viruses.\n                  <\/jats:p>","DOI":"10.1172\/jci178089","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T16:01:02Z","timestamp":1758038462000},"source":"Crossref","is-referenced-by-count":2,"title":["A liver-infiltrating CD4+ Tfh1 cell response predicts HCV control, hepatitis, and seroconversion during acute infection"],"prefix":"10.1172","volume":"135","author":[{"given":"Heather","family":"Blasczyk","sequence":"first","affiliation":[{"name":"The Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Bremer","sequence":"additional","affiliation":[{"name":"The Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Phelps","sequence":"additional","affiliation":[{"name":"The Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Bowen","sequence":"additional","affiliation":[{"name":"The Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, Ohio, 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