CD4+ T cell help during early acute hepacivirus infection is critical for viral clearance and the generation of a liver-homing CD103+CD49a+ effector CD8+ T cell subset.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

CD8-Positive T-Lymphocytes*/immunology ; CD4-Positive T-Lymphocytes*/immunology ; Liver*/immunology ; Liver*/virology ; Hepacivirus*/immunology ; Antigens, CD*/metabolism ; Antigens, CD*/immunology ; Hepatitis C*/immunology ; Hepatitis C*/virology ; Integrin alpha Chains*/metabolism ; Integrin alpha Chains*/immunology; Animals ; Mice ; Mice, Inbred C57BL ; Integrin alpha1/immunology ; Integrin alpha1/metabolism ; Disease Models, Animal ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism

Competing Interests: The authors have declared that no competing interests exist.
In hepatitis C virus (HCV) infection, CD4+ and CD8+ T cells are crucial for viral control. However, a detailed understanding of the kinetic of CD4+ T cell help and its role in the generation of different CD8+ T cell subsets during acute infection is lacking. The absence of a small HCV animal model has impeded mechanistic studies of hepatic antiviral T cell immunity and HCV vaccine development. In this study, we used a recently developed HCV-related rodent hepacivirus infection mouse model to investigate the impact of CD4+ T cell help on the hepatic CD8+ T cell response and viral clearance during hepacivirus infection in vivo. Our results revealed a specific kinetic of CD4+ T cell dependency during acute infection. Early CD4+ T cell help was essential for CD8+ T cell priming and viral clearance, while CD4+ T cells became dispensable during later stages of acute infection. Effector CD8+ T cells directly mediated timely hepacivirus clearance. An analysis of hepatic CD8+ T cells specific for two different viral epitopes revealed the induction of subsets of liver-homing CD103+CD49a+ and CD103-CD49a+ effector CD8+ T cells with elevated IFN-γ and TNF-α production. CD103+CD49a+ T cells further persisted as tissue-resident memory subsets. A lack of CD4+ T cell help and CD40L-CD40 interactions resulted in reduced effector functions and phenotypical changes in effector CD8+ T cells and a specific loss of the CD103+CD49a+ subset. In summary, our study shows that early CD4+ T cell help through CD40L signaling is essential for priming functional effector CD8+ T cell subsets, including unique liver-homing subsets, and hepacivirus clearance.
(Copyright: © 2024 Lopez-Scarim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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P30 CA013330 United States CA NCI NIH HHS; R01 AI170725 United States AI NIAID NIH HHS; T32 GM007491 United States GM NIGMS NIH HHS

0 (Antigens, CD)
0 (alpha E integrins)
0 (Integrin alpha Chains)
0 (Integrin alpha1)

Date Created: 20241011 Date Completed: 20241023 Latest Revision: 20241031

20250114

PMC11498735

10.1371/journal.ppat.1012615

39392861