A liver-infiltrating CD4⁺ Tfh1 cell response predicts HCV control, hepatitis, and seroconversion during acute infection

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Abstract

Sustained CD4+ T cell immunity is required for resolution of acute hepatitis C virus (HCV) infection, but the response remains poorly characterized. Here, circulating CD4+ 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-γ 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 ADGRG1 (GPR56), ZNF683 (Hobit), and KLRB1 (CD161) were also expressed. HCV-specific PD-1hiICOShi CD4+ Tfh1-like cells were enriched in liver, suggesting the potential for B and CD8+ T cell help at the site of virus replication. Most circulating and intrahepatic PD-1hiICOShi CD4+ Tfh1-like cells did not express CXCR5 and therefore resembled CXCR5–CXCL13+ peripheral helper cells that infiltrate tumors and tissues inflamed by autoimmunity. PD-1hiICOShi CD4+ Tfh1-like cells also peaked after hepatitis A virus infection, but the response was accelerated by several weeks compared with HCV infection. The PD-1hiICOShi phenotype and temporal association between the peak response and alanine aminotransferase may provide markers to guide human studies of CD4+ T cell immunity against HCV and other hepatotropic viruses.

Authors

Heather Blasczyk, William Bremer, Christopher C. Phelps, Yan Zhou, David G. Bowen, Zhaohui Xu, Robert Lanford, Naglaa H. Shoukry, Arash Grakoui, Nicole Skinner, Christopher M. Walker